Compounds

ABSTRACT

The present invention relates to substituted bis-arylsulfonamide and arylsulfonamide compounds of the general formula (I) or the formula (II), which compounds are potentially useful for the prophylaxis and treatment of medical conditions relating to obesity, type II diabetes and/or disorders of the central nervous system

RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.10/144,677, filed on May 13, 2002, now U.S. Pat. No. 6,969,710 whichclaims the benefit of Swedish application number 0101659-1, filed on May11, 2001, Swedish application number 0101660-9, filed on May 11, 2001,Swedish application number 0101958-7, filed on Jun. 5, 2001, U.S.provisional application No. 60/294,102, filed on May 29, 2001, and U.S.provisional application No. 60/294,132, filed on May 29, 2001, theentire contents of each of these prior applications are incorporatedherein by reference.

TECHNICAL FIELD

The present invention relates to substituted bis-arylsulfonamide andarylsulfonamide compounds, to pharmaceutical compositions comprisingthese compounds, and to the use of the compounds for the prophylaxis andtreatment of medical conditions relating to obesity, type II diabetesand/or disorders of the central nervous system.

BACKGROUND

Obesity is a condition characterized by an increase in body fat contentresulting in excess body weight above accepted norms. Obesity is themost important nutritional disorder in the western world and representsa major health problem in all industrialized countries. This disorderleads to increased mortality due to increased incidences of diseasessuch as cardiovascular disease, digestive disease, respiratory disease,cancer and type II diabetes. Searching for compounds, which reduce bodyweight has been going on for many decades. One line of research has beenactivation of serotonergic systems, either by direct activation ofserotonin receptor subtypes or by inhibiting serotonin reuptake. Theexact receptor subtype profile required is however not known.

Serotonin (5-hydroxytryptamine or 5-HT), a key transmitter of theperipheral and central nervous system, modulates a wide range ofphysiological and pathological functions, including anxiety, sleepregulation, aggression, feeding and depression. Multiple serotoninreceptor subtypes have been identified and cloned. One of these, the5-HT₆ receptor, was cloned by several groups in 1993 (Ruat, M. et al.(1993) Biochem. Biophys. Res. Commun.193: 268-276; Sebben, M. et al.(1994) NeuroReport 5: 2553-2557). This receptor is positively coupled toadenylyl cyclase and displays affinity for antidepressants such asclozapine. Recently, the effect of 5-HT₆ antagonist and 5-HT₆ antisenseoligonucleotides to reduce food intake in rats has been reported(Bentley, J. C. et al. (1999) Br J Pharmac. Suppl. 126, P66; Bentley, J.C. et al. (1997) J. Psychopharmacol. Suppl. A64, 255).

Compounds with enhanced affinity and selectivity for the 5-HT₆ receptorhave been identified, e.g. in WO 00/34242 and by Isaac, M. et al. (2000)6-Bicyclopiperazinyl-1-arysulfonylindoles and6-Bicyclopiperidinyl-1-arylsulfonylindoles derivatives as novel, potentand selective 5-HT₆ receptor antagonists. Bioorganic & MedicinalChemistry Letters 10: 1719-1721.

DISCLOSURE OF THE INVENTION

It has surprisingly been found that the compounds of formula (I) and(II) show affinity for the 5-HT₆ receptor as antagonists at a lownanomolar range. Compounds according to the invention and theirpharmaceutically acceptable salts have 5-HT₆ receptor antagonistactivity and are believed to be of potential use in the treatment orprophylaxis of obesity and type II diabetes, as well as in the treatmentor prophylaxis of disorders of the central nervous system such asanxiety, depression, panic attacks, memory disorders, sleep disorders,binge disorders, migraine, anorexia, bulimia, obsessive compulsivedisorders, psychoses, Alzheimer's disease, Parkinson's disease,Huntington's chorea and/or schizophrenia, drug abuse, Attention DeficitHyperactive Disorders (ADHD).

Definitions

Unless otherwise stated or indicated, the following definitions shallapply throughout the specification and the appended claims:

The term “C₁₋₆ alkyl” denotes a straight or branched alkyl group havingfrom 1 to 6 carbon atoms. Examples of said lower alkyl include methyl,ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl andstraight- and branched-chain pentyl and hexyl.

The term “C₁₋₆ alkoxy” denotes a straight or branched alkoxy grouphaving from 1 to 6 carbon atoms. Examples of said lower alkoxy includemethoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy,sec-butoxy, t-butoxy and straight- and branched-chain pentoxy andhexoxy.

The term “halogen” shall mean fluorine, chlorine, bromine or iodine.

The terms “C₄₋₆ cycloalkyl” and “C₃₋₇ cycloalkyl” denote a cyclic alkylgroup having a ring size from C₄ to C₆ or from C₃ to C₇, respectively.Examples of said cycloalkyl include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, methylcyclohexyl and cycloheptyl.

Compounds of Formula I

In a first aspect, this invention provides a compound of the generalformula (I)

or a pharmaceutically acceptable salt thereof, wherein

-   -   X is

-   -   R¹ and R³ are independently    -   (a) H    -   (b) C₁₋₆ alkyl,    -   (c) C₁₋₆ alkoxy,    -   (d) straight or branched C₁₋₆ hydroxyalkyl,    -   (e) straight or branched C₁₋₆ alkylhalides; or    -   (f) a group Ar;    -   Ar is    -   (a) phenyl,    -   (b) 1-naphthyl,    -   (c) 2-naphthyl,    -   (d) benzyl,    -   (e) cinnamoyl,    -   (f) a 5 to 7-membered, aromatic, partially or completely        saturated, heterocyclic ring containing 1 to 4 heteroatoms,        selected from oxygen, nitrogen and sulfur, or    -   (g) a bicyclic ring system consisting of two heterocyclic rings        as defined under (f), or a bicyclic ring system consisting of        one benzene ring and one heterocyclic ring as defined under (f);    -   alternatively, R¹ and R³ are linked to form a group (CH₂)₂O,        (CH₂)₄O, or (CH₂)₃₋₅ in formula (Ib);

optionally, the group Ar is substituted with

-   -   (a) Y, or    -   (b) a 5 to 7-membered, partially or completely saturated,        heterocyclic ring each containing 1 to 4 heteroatoms selected        from oxygen, nitrogen or sulfur;    -   Y is    -   (a) H,    -   (b) halogen,    -   (c) C₁₋₆ alkyl,    -   (d) CF₃,    -   (e) hydroxy,    -   (f) C₁₋₆ alkoxy,    -   (g) C₁₋₄ alkenyl;    -   (h) phenyl;    -   (i) phenoxy,    -   (j) benzyloxy,    -   (k) benzoyl,    -   (l) OCF₃,    -   (m) CN,    -   (n) straight or branched C₁₋₆ hydroxyalkyl,    -   (o) straight or branched C₁₋₆ alkylhalides,    -   (p) NH₂,    -   (q) NHR⁶,    -   (r) NR⁶R⁷,    -   (s) NO₂,    -   (t) —CONR⁶R⁷,    -   (u) NHSO₂R⁶,    -   (v) NR⁶COR⁷    -   (x) SO₂NR⁶R⁷,    -   (z) —C(═O)R⁶,    -   (aa) —CO₂R⁶, or    -   (ab) S(O)_(n)R⁶; wherein n is 0, 1, 2 or 3;    -   R² and R⁴ are independently:    -   (a) —SO₂R¹,    -   (b) H,    -   (c) C₁₋₆ alkyl,    -   (d) C₁-C₃ alkenyl,    -   (e) C₁-C₃ alkylaryl,    -   (f) Ar as defined above for R¹,    -   (g) —C(═O)R⁶,    -   (h) —C(O)NR⁶ R⁷,    -   (i) —C(S)NR⁶R⁷,    -   (j) —CO₂R⁶;    -   (k) —C(S)R⁶;    -   (l) straight or branched C₁₋₆ hydroxyalkyl, or    -   (m) straight or branched C₁₋₆ alkylhalides;    -   alternatively, R² and R⁴ are linked to form a group (CH₂)₂O,        (CH₂)₄O, or (CH₂)₃₋₅ in formula (Ia);    -   R⁵ is selected from the group consisting of the following        chemical groups:

R⁶ and R⁷ are independently

-   -   (a) H,    -   (b) C₁₋₆ alkyl,    -   (c) C₃₋₇ cycloalkyl, or    -   (d) Ar, as defined above in R¹;    -   alternatively, R⁶ and R⁷ are linked to form a group (CH₂)₂O,        (CH₂)₄O or (CH₂)₃₋₅;    -   R⁸ is    -   (a) H, or    -   (b) C₁₋₆ alkyl.

In one aspect, Ar is a 5 to 7-membered aromatic heterocyclic ringcontaining 1 to 4 heteroatoms, selected from oxygen, nitrogen andsulfur, such as isoxazolyl, benzoxadiazolyl, quinolinyl, or thienyl.

Preferred compounds of the general formula (I) are those wherein:

-   -   X is

-   -   R¹ is    -   (e) a group Ar; or    -   (f) C₁₋₆ alkyl

Ar is

-   -   (a) phenyl,    -   (b) 1-naphthyl,    -   (c) 2-naphthyl, or    -   (f) a 5 to 7-membered, partially or completely saturated,        heterocyclic ring containing 1 to 4 heteroatoms, selected from        oxygen, nitrogen and sulfur;    -   the group Ar is substituted with Y, wherein Y is    -   (a) H,    -   (b) halogen,    -   (c) C₁₋₆ alkyl,    -   (d) CF₃,    -   (f) C₁₋₆ alkoxy,    -   (g) C₁₋₄ alkenyl;    -   (h) phenyl;    -   (l) OCF₃, or    -   (n) straight or branched C₁₋₆ hydroxyalkyl;    -   the group

is attached to the phenyl ring in 2-position or in 3-position;

-   -   R² and R⁴ are indipendently    -   (a) H    -   (b) C1-3 alkyl, in particular methyl or ethyl    -   (c) —SO₂R¹; or    -   (d) are linked to form a group (CH₂)₄O    -   R⁵ is selected from the group consisting of the following        chemical groups:

-   -   -   wherein R⁸ is        -   (a) H, or        -   (b) C₁₋₆ alkyl, in particular methyl.

    -   R⁶ and R⁷ are independently

    -   (a) H,

    -   (b) C₁₋₆ alkyl,

    -   (c) C₃₋₇ cycloalkyl, or

    -   (d) Ar.

Exemplary compounds are listed below:

-   -   N-[2-[ethyl(phenylsulfonyl)amino]4-(4-methyl-1-piperazinyl)phenyl]benzenesulfonamide        hydrochloride    -   3-fluoro-N-[2-{[(3-fluorophenyl)sulfonyl]amino}-4-(4-methyl-1-piperazinyl)phenyl]benzenesulfonamide        hydrochloride    -   N-{4-(4-methyl-1-piperazinyl)-2-[(8-quinolinylsulfonyl)amino]phenyl}-8-quinolinesulfonamide        hydrochloride hydrochloride    -   4-methyl-N-{4-(4-methyl-1-piperazinyl)-2-[(methylsulfonyl)amino]phenyl}benzenesulfonamide        hydrochloride    -   N-{4-(1-piperazinyl)-2-[(phenylsulfonyl)amino]phenyl}-1-naphthalenesulfonamide        hydrochloride    -   N-[2-[(phenylsulfonyl)amino]-4-(1-piperazinyl)phenyl]-8-quinolinesulfonamide        hydrochloride    -   2-methyl-N-[2-[(phenylsulfonyl)amino]-4-(1-piperazinyl)phenyl]benzenesulfonamide        hydrochloride    -   4-butoxy-N-[2-[(phenylsulfonyl)amino]-4-(1-piperazinyl)phenyl]benzenesulfonamide        hydrochloride    -   5-fluoro-2-methyl-N-[2-[(phenylsulfonyl)amino]-4-(1-piperazinyl)phenyl]benzenesulfonamide        hydrochloride    -   2-methoxy-4-methyl-N-[2-[(phenylsulfonyl)amino]-4-(1-piperazinyl)phenyl]benzenesulfonamide        hydrochloride    -   N-{4-(1,4-diazepan-1-yl)-2-[(phenylsulfonyl)amino]phenyl}benzenesulfonamide        hydrochloride    -   N-{5-(1,4-diazepan-1-yl)-2-[(phenylsulfonyl)amino]phenyl}-N-ethylbenzenesulfonamide        hydrochloride    -   N-{4-(1,4-diazepan-1-yl)-2-[(phenylsulfonyl)amino]phenyl}-2-naphthalenesulfonamide        hydrochloride    -   N-{4-(1,4-diazepan-1-yl)-2-[methyl(phenylsulfonyl)amino]phenyl}benzenesulfonamide        hydrochloride    -   N-{4-(1,4-diazepan-1-yl)-2-[(methylsulfonyl)amino]phenyl}-1-naphthalenesulfonamide        hydrochloride    -   N-{4-(1,4-diazepan-1-yl)-2-[(methylsulfonyl)amino]phenyl}-2-naphthalenesulfonamide        hydrochloride    -   N-{4-(1,4-diazepan-1-yl)-2-[methyl(methylsulfonyl)amino]phenyl}-1-naphthalenesulfonamide        hydrochloride    -   N-{4-(1,4-diazepan-1-yl)-2-[(phenylsulfonyl)amino]phenyl}-8-quinolinesulfonamide        hydrochloride    -   N-{4-(1,4-diazepan-1-yl)-2-[(phenylsulfonyl)amino]phenyl}-2,4,6-trimethylbenzenesulfonamide        hydrochloride    -   N-{4-(1,4-diazepan-1-yl)-2-[(phenylsulfonyl)amino]phenyl}-4-methylbenzenesulfonamide        hydrochloride    -   N-{4-(1,4-diazepan-1-yl)-2-[(phenylsulfonyl)amino]phenyl}-2-methylbenzenesulfonamide        hydrochloride    -   N-{4-(1,4-diazepan-1-yl)-2-[(phenylsulfonyl)amino]phenyl}-5-fluoro-2-methylbenzenesulfonamide        hydrochloride    -   N-{5-(1,4-diazepan-1-yl)-2-[methyl(phenylsulfonyl)amino]phenyl}-4-methylbenzenesulfonamide        hydrochloride    -   3-amino-4-(1,4-diazepan-1-yl)-N-(2-methoxyphenyl)benzenesulfonamide        hydrochloride    -   3-amino-N-(3-chlorophenyl)-4-(1,4-diazepan-1-yl)benzenesulfonamide        hydrochloride    -   3-amino-N-(2-chlorophenyl)-4-(1,4-diazepan-1-yl)benzenesulfonamide        hydrochloride    -   3-amino-4-(4-methyl-1,4-diazepan-1-yl)-N-phenylbenzenesulfonamide        hydrochloride    -   3-amino-N-(2-methoxyphenyl)-4-(1-piperazinyl)benzenesulfonamide        hydrochloride    -   2-[1,4]Diazepan-1-yl-5-(3,4-dihydro-1H-isoquinoline-2-sulfonyl)-aniline        dihydrochloride hydrochloride    -   3-Amino-2-chloro-N-naphthalen-1-yl-4-piperazin-1-yl-benzenesulfonamide,        hydrochloride hydrochloride

TABLE I Compounds of the formula I wherein R² is —SO₂—R^(1′)

Name R¹ R^(1′) R³ R⁴ R⁵ 1N-[2-{ethyl[(3-fluorophenyl)sulfonyl]amino}-4-(4-methyl-1-piperazinyl)phenyl]-3-fluorobenzenesulfonamide

H Et

2N-[2-[ethyl(phenylsulfonyl)amino]-4-(4-methyl-1-piperazinyl)phenyl]benzenesulfonamide

H Et

33-fluoro-N-[2-{[(3-fluorophenyl)sulfonyl]amino}-4-(4-methyl-1-piperazinyl)phenyl]benzenesulfonamide

H H

4N-{4-(4-methyl-1-piperazinyl)-2-[(8-quinolinylsulfonyl)amino]phenyl}-8-quinolinesulfonamidehydrochloride

H H

5N-[2-chloro-4-({4-(4-methyl-1-piperazinyl)-2-[(phenylsulfonyl)amino]anilino}sulfonyl)phenyl]acetamide

H H

63,4-dimethoxy-N-{4-(4-methyl-1-piperazinyl)-2-[(phenylsulfonyl)amino]phenyl}benzenesulfonamide

H H

73-methoxy-4-methyl-N-{4-(4-methyl-1-piperazinyl)-2-[(phenylsulfonyl)amino]phenyl}benzenesulfonamide

H H

84-methyl-N-{4-(4-methyl-1-piperazinyl)-2-[(methylsulfonyl)amino]phenyl}benzenesulfonamide

—CH₃ H H

93,4-dimethoxy-N-{4-(4-methyl-1-piperazinyl)-2-[(methylsulfonyl)amino]phenyl}benzenesulfonamide

—CH₃ H H

103-cyano-N-{4-(4-methyl-1-piperazinyl)-2-[(methylsulfonyl)amino]phenyl}benzenesulfonamide

—CH₃ H H

11N-{4-(1-piperazinyl)-2-[(phenylsulfonyl)amino]phenyl}-1-naphthalenesulfonamide

H H

125-(dimethylamino)-N-{4-(1-piperazinyl)-2-[(phenylsulfonyl)amino]phenyl}-1-naphthalenesulfonamide

H H

13N-[2-[(phenylsulfonyl)amino]-4-(1-piperazinyl)phenyl]-8-quinolinesulfonamide

H H

142,4,6-trimethyl-N-[2-[(phenylsulfonyl)amino]-4-(1-piperazinyl)phenyl]benzenesulfonamide

H H

154-methyl-N-[2-[(phenylsulfonyl)amino]-4-(1-piperazinyl)phenyl]benzenesulfonamide

H H

16N-[2-({[(E)-2-phenylethenyl]sulfonyl}amino)-5-(1-piperazinyl)phenyl]benzenesulfonamide

H H

172,5-dimethoxy-N-[2-[(phenylsulfonyl)amino]-4-(1-piperazinyl)phenyl]benzenesulfonamide

H H

182-methyl-N-[2-[(phenylsulfonyl)amino]-4-(1-piperazinyl)phenyl]benzenesulfonamide

H H

192,4-difluoro-N-[2-[(phenylsulfonyl)amino]-4-(1-piperazinyl)phenyl]benzenesulfonamide

H H

204-butoxy-N-[2-[(phenylsulfonyl)amino]-4-(1-piperazinyl)phenyl]benzenesulfonamide

H H

213,5-dimethyl-N-[2-[(phenylsulfonyl)amino]-4-(1-piperazinyl)phenyl]-4-isoxazolesulfonamide

H H

225-fluoro-2-methyl-N-[2-[(phenylsulfonyl)amino]-4-(1-piperazinyl)phenyl]benzenesulfonamide

H H

234-(methylsulfonyl)-N-[2-[(phenylsulfonyl)amino]-4-(1-piperazinyl)phenyl]benzenesulfonamide

H H

242-(methylsulfonyl)-N-[2-[(phenylsulfonyl)amino]-4-(1-piperazinyl)phenyl]benzenesulfonamide

H H

252-methoxy-4-methyl-N-[2-[(phenylsulfonyl)amino]-4-(1-piperazinyl)phenyl]benzenesulfonamide

H H

264-methoxy-2-methyl-N-[2-[(phenylsulfonyl)amino]-4-(1-piperazinyl)phenyl]benzenesulfonamide

H H

27N-{4-(1,4-diazepan-1-yl)-2-[(phenylsulfonyl)amino]phenyl}benzenesulfonamide

H H

28N-(4-(1,4-diazepan-1-yl)-2-{[(3-fluorophenyl)sulfonyl]-amino}phenyl)-3-fluorobenzenesulfonamide

H H

29N-{5-(1,4-diazepan-1-yl)-2-[(phenylsulfonyl)amino]phenyl}-N-ethylbenzenesulfonamide

H Et

30N-{5-(1,4-diazepan-1-yl)-2-[(methylsulfonyl)amino]phenyl}benzenesulfonamideMe

H H

31N-{5-(1,4-diazepan-1-yl)-2-[(ethylsulfonyl)amino]phenyl}benzenesulfonamideEt

H H

32N-{4-(1,4-diazepan-1-yl)-2-[(phenylsulfonyl)amino]phenyl}[1,1′-biphenyl]-4-sulfonamide

H H

33N-{4-(1,4-diazepan-1-yl)-2-[(phenylsulfonyl)amino]phenyl}-2,1,3-benzoxadiazole-4-sulfonamide

H H

34N-{4-(1,4-diazepan-1-yl)-2-[(phenylsulfonyl)amino]phenyl}-2-naphthalenesulfonamide

H H

35N-{4-(1,4-diazepan-1-yl)-2-[(methylsulfonyl)amino]phenyl}benzenesulfonamide

Me H H

36N-{4-(1,4-diazepan-1-yl)-2-[methyl(methylsulfonyl)amino]phenyl}benzenesulfonamidePHA-526210A

Me H Me

37N-{4-(1,4-diazepan-1-yl)-2-[(methylsulfonyl)amino]phenyl}-N-methylbenzenesulfonamide

Me Me H

38N-{4-(1,4-diazepan-1-yl)-2-(methyl(phenylsulfonyl)amino]phenyl}benzenesulfonamide

H Me

39N-{4-(1,4-diazepan-1-yl)-2-[(methylsulfonyl)amino]phenyl}-1-naphthalenesulfonamide

Me H H

40N-{4-(1,4-diazepan-1-yl)-2-[(methylsulfonyl)amino]phenyl}-2-naphthalenesulfonamide

Me H H

41N-{4-(1,4-diazepan-1-yl)-2-[(methylsulfonyl)amino]phenyl}-4-fluorobenzenesulfonamide

Me H H

42N-{4-(1,4-diazepan-1-yl)-2-[(methylsulfonyl)amino]phenyl}-4-nitrobenzenesulfonamide

Me H H

43N-{4-(1,4-diazepan-1-yl)-2-[(methylsulfonyl)amino]phenyl}-3-(trifluoromethyl)benzenesulfonamide

Me H H

44N-{4-(1,4-diazepan-1-yl)-2-[(methylsulfonyl)amino]phenyl}-2-methylbenzenesulfonamide

Me H H

45N-{4-(1,4-diazepan-1-yl)-2-[(methylsulfonyl)amino]phenyl}-4-(trifluoromethoxy)benzenesulfonamide

Me H H

46N-{4-(1,4-diazepan-1-yl)-2-[(methylsulfonyl)aminol]phenyl}-3,5-dimethyl-4-isoxazolesulfonamide

Me H H

47N-{4-(1,4-diazepan-1-yl)-2-[(methylsulfonyl)amino]phenyl}-3-methoxybenzenesulfonamide

Me H H

48N-{4-(1,4-diazepan-1-yl)-2-[(methylsulfonyl)amino]phenyl}-4-methylbenzenesulfonamide

Me H H

49N-{4-(1,4-diazepan-1-yl)-2-[ethyl(methylsulfonyl)amino]phenyl}-4-methylbenzenesulfonamide

Me H Et

50N-{4-(1,4-diazepan-1-yl)-2-[ethyl(methylsulfonyl)amino]phenyl}-3,4-dimethoxybenzenesulfonamide

Me H Et

51N-{4-(1,4-diazepan-1-yl)-2-[ethyl(methylsulfonyl)amino]phenyl}-7-quinolinesulfonamide

Me H Et

52N-{4-(1,4-diazepan-1-yl)-2-[methyl(methylsulfonyl)amino]phenyl}-4-methylbenzenesulfonamide

Me H Me

53N-{4-(1,4-diazepan-1-yl)-2-[methyl(methylsulfonyl)amino]phenyl}-1-naphthalenesulfonamide

Me H Me

54N-{4-(1,4-diazepan-1-yl)-2-[methyl(methylsulfonyl)amino]phenyl}-5-(2-pyridinyl)-2-thiophenesulfonamide

Me H Me

55N-{4-(1,4-diazepan-1-yl)-2-[(phenylsulfonyl)amino]phenyl}-1-naphthalenesulfonamide

H H

56N-{4-(1,4-diazepan-1-yl)-2-[(phenylsulfonyl)amino]phenyl}-5-(dimethylamino)-1-naphthalenesulfonamide

H H

57N-{4-(1,4-diazepan-1-yl)-2-[(phenylsulfonyl)amino]phenyl}-8-quinolinesulfonamide

H H

58N-{4-(1,4-diazepan-1-yl)-2-[(phenylsulfonyl)amino]phenyl}-2,4,6-trimethylbenzenesulfonamide

H H

59N-{4-(1,4-diazepan-1-yl)-2-[(phenylsulfonyl)amino]phenyl}-4-methylbenzenesulfonamide

H H

60N-[5-(1,4-diazepan-1-yl)-2-({[(E)-2-phenylethenyl]sulfonyl}amino)phenyl]benzenesulfonamide

H H

61N-{4-(1,4-diazepan-1-yl)-2-[(phenylsulfonyl)amino]phenyl}-2,5-dimethoxybenzenesulfonamide

H H

62N-{4-(1,4-diazepan-1-yl)-2-[(phenylsulfonyl)amino]phenyl}-2-methylbenzenesulfonamide

H H

634-butoxy-N-{4-(1,4-diazepan-1-yl)-2-[(phenylsulfonyl)amino]phenyl}benzenesulfonamide

H H

63N-{4-(1,4-diazepan-1-yl)-2-[(phenylsulfonyl)amino]phenyl}-3,5-dimethyl-4-isoxazolesulfonamide

H H

65N-{4-(1,4-diazepan-1-yl)-2-[(phenylsulfonyl)amino]phenyl}-5-fluoro-2-methylbenzenesulfonamide

H H

66N-{4-(1,4-diazepan-1-yl)-2-[(phenylsulfonyl)amino]phenyl}-4-(methylsulfonyl)benzenesulfonamide

H H

67N-{4-(1,4-diazepan-1-yl)-2-[(methylsulfonyl)amino]phenyl]-N-methylbenzenesulfonamide

Me Me H

68N-{5-(1,4-diazepan-1-yl)-2-[methyl(phenylsulfonyl)amino]phenyl}-4-methylbenzenesulfonamide

Me H

TABLE II Compounds of the formula Ia

Name R¹ R³ R² R⁴ R⁵ 69N-[2-amino-4-(1-piperazinyl)phenyl]-3-fluorobenzenesulfonamide

H H H

70 N-[2-(ethylamino)-4-(1-piperazinyl)phenyl]-3-fluorobenzenesulfonamide

H H Et

Compounds of the Formula II

In a further aspect, the invention provides a compound having thegeneral formula (II)

or a pharmaceutically acceptable salt thereof, wherein

-   -   R⁹, R¹² and R¹⁴ are H; or    -   two of R⁹, R¹² and R¹⁴ are H; and the remaining of R⁹, R¹² and        R¹⁴ is    -   (a) —NH₂,    -   (b) —NHR⁶,    -   (c) —NR⁶R⁷,    -   (d) —N(CO)R⁶,    -   (e) —N(CS)R⁶, or    -   (f) —NO₂;    -   R¹⁰ and R¹¹ is a group R³ or R¹ as defined for Formula I;    -   R¹³ is    -   (a) homopiperazine,    -   (b) methylhomopiperazine or    -   (c) a group R⁵ as defined for Formula I, wherein R⁸ is as        defined for Formula I;    -   Y is as defined for Formula I.

Preferred compounds of the general formula (II) are those wherein:

-   -   R¹³ is    -   (a) homopiperazine,    -   (b) methylhomopiperazine, or    -   (c) a group R⁵ selected from

-   -   R⁸ is    -   (a) H, or    -   (b) C₁₋₆ alkyl, in particular methyl;

TABLE III Compounds of the formula (II) wherein R¹⁰, R¹⁴ and Y are H

Name R⁹ R¹¹ R¹² R¹³ 714-chloro-N-[5-(4-methyl-1,4-diazepan-1-yl)-2-nitrophenyl]benzenesulfonamide—NO₂

H

72 N-[2-amino-5-(1,4-diazepan-1-yl)phenyl]benzenesulfonamide —NH₂

H

73 N-[2-amino-5-(4-methyl-1,4-diazepan-1-yl)phenyl]benzenesulfonamide—NH₂

H

74 N-[4-nitro-3-(1-piperazinyl)phenyl]benzenesulfonamide H

—NO₂

75 N-[4-amino-3-(1-piperazinyl)phenyl]benzenesulfonamide H

—NH₂

TABLE IV Compounds of formula (I) wherein Y and group —N-R² R⁴, isassigned as group R in the structure below and wherein R⁵ is a group

Name R¹ R³ —R R⁸ 763-amino-4-(1,4-diazepan-1-yl)-N-(4-methoxyphenyl)benzenesulfonamide

H —NH₂ H 773-amino-4-(1,4-diazepan-1-yl)-N-(3-methoxyphenyl)benzenesulfonamide

H —NH₂ H 783-amino-4-(1,4-diazepan-1-yl)-N-(2-methoxyphenyl)benzenesulfonamide

H —NH₂ H 793-amino-4-(1,4-diazepan-1-yl)-N-(3-fluorophenyl)benzenesulfonamide

H —NH₂ H 803-amino-4-(1,4-diazepan-1-yl)-N-methyl-N-phenylbenzenesulfonamide

—CH₃ —NH₂ H 813-amino-4-(1,4-diazepan-1-yl)-N-(4-isopropylphenyl)benzenesulfonamide

H —NH₂ H 823-amino-4-(1,4-diazepan-1-yl)-N-(4-methylphenyl)benzenesulfonamide

H —NH₂ H 833-amino-4-(1,4-diazepan-1-yl)-N-(2,5-dimethylphenyl)benzenesulfonamide

H —NH₂ H 843-amino-N-(3-chlorophenyl)-4-(1,4-dizepan-1-yl)benzenesulfonarnide

H —NH₂ H 853-amino-N-(2-chlorophenyl)-4-(1,4-diazepan-1-yl)benzenesulfonamide

H —NH₂ H 863-amino-N-(2,4-dichlorophenyl)-4-(1,4-diazepan-1-yl)benzenesulfonamide

H —NH₂ H 873-amino-N-(2-methyl-5-chloro-phenyl)-4-(1,4-diazepan-1-yl)benzenesulfonamide

H —NH₂ H 883-amino-N-(2-methyl-3-chloro-phenyl)-4-(1,4-diazepan-1-yl)benzenesulfonamide

H —NH₂ H 893-amino-N-(4-trifluoro-phenyl)-4-(1,4-diazepan-1-yl)benzenesulfonamide

H —NH₂ H 903-amino-N-(4-fluorophenyl)-4-(1,4-diazepan-1-yl)benzenesulfonamide

H —NH₂ H 913-amino-N-(2-fluorophenyl)-4-(1,4-diazepan-1-yl)bezenesulfonamide

H —NH₂ H 923-amino-4-(4-methyl-1,4-diazepan-1-yl)-N-phenylbenzenesulfonamide

H —NH₂ —CH₃ 93 4-(1,4-diazepan-1-yl)-3-nitro-N-phenylbenzenesulfonamide

H —NO₂ H 94 3-amino-4-(1,4-diazepan-1-yl)-N-phenylbenzenesulfonamide

H —NH₂ H 95 2-(1,4-diazepan-1-yl)-5-(4-morpholinylsulfonyl)phenylamine

—NH₂ H 964-(1,4-diazepan-1-yl)-N-phenyl-3-[(phenylsulfonyl)amino]benzenesulfonamide

H

H 974-(1,4-diazepan-1-yl)-N-phenyl-3-[(methylsulfonyl)amino]benzenesulfonamide

H

H

TABLE V Compounds of formula (I) wherein Y, R³, R² and R⁴ are H

Name R¹ R⁵ 983-amino-N-(3-chlorophenyl)-4-(4-methyl-1-piperazinyl)benzenesulfonamide

993-amino-N-(2-methoxyphenyl)-4-(4-methyl-1-piperazinyl)benzenesulfonamide

100 3-amino-N-(2-methoxyphenyl)-4-(1-piperazinyl)benzenesulfonamide

1013-amino-N-(2-methoxyphenyl)-4-(3-methyl-1-lpiperazinyl)benzenesulfonamide

1023-Amino-4-(hexahydro-pyrrolo[1,2-a]pyrazin-2-yl)-N-(2-methoxyphenyl)-benzenesulfonamide

103 3-Amino-N-phenyl-4-piperazin-1-yl-benzenesulfonamide hydrochloride

1043-Amino-4-(3-methyl-piperazin-1-yl)-N-phenyl-benzenesulfonamidehydrochloride

1053-Amino-4-(4-ethyl-piperazin-1-yl)-N-phenyl-benzenesulfonamidehydrochloride

1063-Amino-4-(hexahydro-pyrrolo[1,2-a]pyrazin-2-yl)-N-phenyl-benzenesulfonamidehydrochloride

1073-Amino-4-(5-methyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-N-phenyl-benzenesulfonamidehydrochloride

1083-Amino-4-(trans-2,5-dimethyl-piperazin-1-yl)-N-(2methoxy-phenyl)benzenesulfonamidehydrochloride

109 2-(3-Amino-4-[1,4]diazepan-1-yl-benzenesulfonyl)-benzamide diaceticacid

1104-[4-(3-Fluoro-2-methoxy-phenylsulfamoyl)-2-amino-phenyl]-[1,4]diazepaneditrifluoroaceticacid

1112-[1,4]Diazepan-1-yl-5-(3,4-dihydro-1H-isoquinoline-2-sulfonyl)-anilinedihydrochloride

1124-[4-(3,4-Dihydro-2H-quinoline-1-sulfonyl)-2-amino-phenyl]-[1,4]diazepaneditrifluoroaceticacid

TABLE VI

Name R¹ R⁵ 1133-Amino-2-chloro-N-naphthalen-1-yl-4-piperazin-1-yl-benzenesulfonamide,hydrochloride

The compounds in the tables are hydrochloride salts, reported ifotherwiseProcesses for Preparation

The compounds according to the invention having two sulfonyl groups wereprepared according to the methods outlined in Schemes 1, 2 and 3.

Depending on the process conditions the end products of the Formula Iare obtained either in neutral or salt form. Both the free base and thesalts of these end products are within the scope of the invention.

Acid addition salts of the new compounds may in a manner known per se betransformed into the free base using basic agents such as alkali or byion exchange. The free base obtained may also form salts with organic orinorganic acids.

In the preparation of acid addition salts, preferably such acids areused which form suitably therapeutically acceptable salts. Examples ofsuch acids are hydrohalogen acids, sulfuric acid, phosphoric acid,nitric acid, aliphatic, alicyclic, aromatic or heterocyclic carboxyl orsulfonic acids, such as formic acid, acetic acid, propionic acid,succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid,citric acid, ascorbic acid, maleic acid, hydroxymaleic acid, pyruvicacid, p-hydroxybensoic acid, embonic acid, methanesulfonic acid,ethanesulfonic acid, hydroxyethanesulfonic acid, halogenbensenesulfonicacid, toluenesulfonic acid, mandelic acid or naphthalenesulfonic acid.

Throughout the specification and the appended claims, a given chemicalformula or name shall encompass all stereo and optical isomers andracemates thereof where such isomers exist. All diastereomeric formspossible (pure enantiomers, tautomers, racemic mixtures and unequalmixtures of two enantiomers) are within the scope of the invention. Suchcompounds can also occur as cis- or trans-, E- or Z- double bond isomerforms. All isomeric forms are contemplated.

Pharmaceutical Formulations

Pharmaceutical formulations are usually prepared by mixing the activesubstance, or a pharmaceutically acceptable salt thereof, withconventional pharmaceutical excipients. The formulations can be furtherprepared by known methods such as granulation, compression,microencapsulation, spray coating, etc.

This invention relates to a method of treating obesity or type IIdiabetes. The method includes administering to a mammal subject (e.g.,human) in need thereof an effective amount of one or more compounds ofthe formula (I) or the formula (II) above. Also winthin the scope ofthis invention is a method for modulating (e.g., inhibiting) 5-HT₆receptor activity. The method includes administering to a mammal in needthereof an effective amount of a compound of the formula (I) or theformula (II) above.

“An effective amount” refers to an amount of a compound which confers atherapeutic effect on the treated subject. The therapeutic effect may beobjective (i.e., measurable by some test or marker) or subjective (i.e.,subject gives an indication of or feels an effect). For clinical use,the compounds of the invention are formulated into pharmaceuticalformulations for oral, rectal, parenteral or other mode ofadministration. Usually the amount of active compounds is between0.1-95% by weight of the preparation, preferably between 0.2-20% byweight in preparations for parenteral use and preferably between 1 and50% by weight in preparations for oral administration.

The typical daily dose of the active substance varies within a widerange and will depend on various factors such as for example theindividual requirement of each patient and the route of administration.In general, oral and parenteral dosages will be in the range of 5 to1000 mg per day of active substance, preferably 50 to 150 mg per day.

The specific examples below are to be construed as merely illustrative,and not limitative of the remainder of the disclosure in any waywhatsoever. Without further elaboration, it is believed that one skilledin the art can, based on the description herein, utilize the presentinvention to its fullest extent. All publications cited herein arehereby incorporated by reference in their entirety.

EXAMPLES

In the following examples, the structure of the prepared compounds wereconfirmed by standard spectroscopic methods and elemental analysisand/or high resolution MS. The NMR data were obtained on a JEOL JNM-EX270, a Bruker 400 DPX or a Bruker DRX 500 spectrometer. IR spectra wereobtained on a Perkin Elmer SPECTRUM 1000 FT-IR spectrometer. Highresolution MS were obtained on a Micromass LCT spectrometer. Elementalanalysis was performed by Mikro Kemi AB Uppsala Sweden. Melting points,when given, were obtained on a Büchi or a Gallenkamp melting pointapparatus and are uncorrected.

Synthesis According to Scheme 1, Method 2 (R=Boc)

Intermediate 1

N-Ethyl-5-fluoro-2-nitroaniline

A suspension of 2,4-difluoro-1-nitrobenzene (0.50 g, 0.003 mmol),ethylamine hydrochloride (0.49 g, 0.006 mmol), K₂CO₃ (1.66 g, 0.012mmol) in acetonitrile (30 mL) was stirred at room temperature for 16hours and then filtered. The filtrate was concentrated and dissolved insmall amount of CHCl₃. Purification by column chromatography on silicausing pentane/diethyl ether 95:5 as eluent gave 0.45 g of a yellowsolid. ¹H NMR (CDCl₃) δ 8.23-8.18 (m, 1H), 8.08 (br s, 1H), 6.49-6.45(m, 1H), 6.38-6.32 (m, 1H), 3.34-3.27 (m, 2H), 1.38 (tr, J=7.22 Hz, 3H);¹³C NMR (CDCl₃) δ 167.55 (d, J_(CF)=255.6 Hz), 147.4 (d, J_(CF)=12.9Hz), 129.91 (d, J_(CF)=12.9 Hz), 128.71 (br s), 103.73 (d, J_(CF)32 24.8Hz), 99.14 (d, J_(CF)=27.6 Hz), 37.88, 14.05; MS (posESI) m/z=found184.0653, calc 184.0648. Anal. (C₁₂H₁₈N₄O₂) C, H, N.

Intermediate 2

N-Ethyl-2-nitro-5-(1-piperazinyl)aniline

A suspension of N-ethyl-5-fluoro-2-nitroaniline (1.5 g, 8.12 mmol),piperazine (0.979 g, 11.37 mmol), K₂CO₃ (3.36 g, 24.3 mmol) in DMF (40mL) was heated in a microwave oven for 1 min at 100 W. The reactionmixture was allowed to cool and then heated for another minute at 100 w.This procedure was repeated 5 times. The suspension was filtered andthen concentrated. The crude oil was purified via flash chromatographyon silica using CHCl₃/MeOH/NH₃ 9:1:0.4% as eluent to give 1.53 g (75%)of a yellow solid. ¹H NMR (CDCl₃) δ 8.30 (br s, 1H), 8.08-8.04 (m, 1H),6.25-6.20 (m, 1H), 5.88-5.86 (m, 1H), 3.39-3.28 (m, 6H), 3.03-2.97 (m,4H), 1.37 (tr, J=7.2 Hz, 3H); ¹³C NMR (CDCl₃) δ 156.27, 147.74, 128.96,124.13, 104.28, 93.34, 48.22, 45.99, 37.73, 14.15; MS (posEI) m/z=250(M⁺); MS (posESI) m/z=found 250.1429, calc 250.1430. Anal (C₁₂H₁₈N₄O₂)C,H,O.

Intermediate 3

tert-Butyl 4-[3-(ethylamino)-4-nitrophenyl]-1-piperazinecarboxylate

To a solution of N-ethyl-2-nitro-5-(1-piperazinyl)aniline (1.020 g,4.075 mmol), and NaOH (0.39 g, 2.45 mmol) in THF:H₂O (64 mL, 1:1) wasadded a solution of di-tertbutyl-dicarbonate (2.67 g, 12.2 mmol) in 5 mLTHF. The solution was stirred at room temperature for 16 hours. Themixture was neutralized with 1 N HCl. The volatiles were removed undervacuum to yield 1.4 g of crude material (98%). ¹H NMR (CDCl₃) δ 8.28 (brs, 1H), 8.13-8.09 (m, 1H), 6.27-6.22 (m, 1H), 6.05-6.02 (m, 1H),3.67-3.61 (m, 4H), 3.45-3.38 (m, 4H), 3.35-3.27 (m, 2H), 1.50 (s, 9H);MS (posESI) m/z=found 350.1951, calc 350.1954.

Intermediate 4

tert-Butyl 4-[4-amino-3-(ethylamino)phenyl]-1-piperazinecarboxylate

To a solution of tert-butyl4-[3-(ethylamino)-4-nitrophenyl]-1-piperazinecarboxylate (1.028 g, 2.93mmol) in 40 mL EtOH:THF (4:1) solvent system was added Raney-Ni (1 mL ofa EtOH suspension) followed by addition hydrazine hydrate (0.734 g,14.67 mmol). The mixture was stirred vigorously for 3 hours and thenfiltered through a Celite pad pretreated with water. The filtrate wasconcentrated and then purified by column chromatography on silica usingCHCl₃/MeOH/NH₃ 9:1:0.4% as eluent to give 0.877 g (93%) of a red oil.The oil was used immediately in the next reaction. HPLC purity >90%; MS(posEI) m/z=320 (M⁺);

Method 1, Scheme 1: General for sulfonylation (R1=Me)

Intermediate 5

N-ethyl-5-(4-methyl-1-piperazinyl)-2-nitroaniline (Method 1, Scheme 1)

N-ethyl-5-(4-methyl-1-piperazinyl)-2-nitroaniline was prepared from2,4-difluoro-1-nitrobenzene and methylpiperazine using the same methoddescribed for N-ethyl-2-nitro-5-(1-piperazinyl)aniline and was obtainedas yellow solid (99%). ¹H NMR (CDCl₃) δ 8.30 (br s, 1H), 8.08-8.04 (m,1H), 6.25-6.20 (m, 1H), 5.89-5.86 (m, 1H), 3.45-3.39 (m,4H), 3.35-3.25(m, 2H), 2.56-2.50 (m, 4H), 2.35 (s, 3H), 1.37 (tr, J=7.2 Hz, 3)); ¹³CNMR δ (CDCl₃) 155.92, 147.72, 128.99, 124.19, 104.30, 94.37, 54.78,47.05, 46.25, 37.73, 14.43; MS (posESI) m/z =found 264.1575, calc264.1586. Anal. (C₁₃H₂₀N₄O₂.0.5 H₂O) C, H, O.

Intermediate 6

N-2-Ethyl-4-(4-methyl-1-piperazinyl)-1,2-benzenediamine (Method 1,Scheme 1)

N-Ethyl-5-(4-methyl-1-piperazinyl)-2-nitroaniline was reduced withRaney-Ni as described previously for the synthesis of tert-butyl4-[4-amino-3-(ethylamino)phenyl]-1-piperazinecarboxylate to giveN-2-ethyl4-(4-methyl-1-piperazinyl)-1,2-benzenediamine (yield >90%) as ared oil. The product is very sensitive to oxidation and was thereforeused immediately in the next reaction step. HPLC purity >90%; MS (posEI)m/z=234 (M⁺);

Example 1

N-[2-{Ethyl[(3-fluorophenyl)sulfonyl]amino}-4-(4-methyl-1-piperazinyl)phenyl]-3-fluorobenzensulfonamidehydrochloride (Method 1, Scheme 1)

To a solution of amineN-2-ethyl4-(4-methyl-1-piperazinyl)-1,2-benzenediamine (0.200 g, 0.853mmol) and pyridine (0.48 mL, 5.97 mmol) in CH₂Cl₂ (8 mL) was added asolution of 3-fluorobenzenesulfonyl chloride (249 mg, 1.28 mmol) inCH₂Cl₂ (2 mL). The mixture was stirred at room temperature for 16 hours.CH₂Cl₂ (10 mL) was added and the mixture was washed with saturatedaqueous NaHCO₃. The organic layer was dried over Na₂SO₄, filtered andconcentrated. Purification by column chromatography (Al₂O₃, EtOAc/MeOH9.5:0.5) gave two products. The first fraction contained 110 mg ofN-[2-{ethyl[(3-fluorophenyl)sulfonyl]amino}-4-(4-methyl-1-piperazinyl)phenyl]-3-fluorobenzensulfonamidehydrochloride. The second fraction contained 100 mg ofN-[2-(ethylamino)-4-(4-methyl-1-piperazinyl)phenyl]-3-fluorobenzenesulfonamidehydrochloride. Both products were converted to the HCl-salts.

N-[2-{ethyl[(3-fluorophenyl)sulfonyl]amino}4-(4-methyl-1-piperazinyl)phenyl]-3-fluorobenzenesulfonamidehydrochloride: ¹H NMR (DMSO-d6) δ 11.14 (br s, 1H), 9.27 (s, 1H),7.75-7.35 (m, 8H), 7.18-7.15 8m, 1H), 6.95-6.90 (m, 1H), 6.07-6.04 (m,1H), 3.47-3.30 (m, 4H), 3.05-2.85 (m, 4H), 2.73 8d, J=4.7 Hz), 0.72 (tr,J=7.2 Hz); ¹³C NMR (CD₃OD) δ 162.65 (d, J_(CF)=5.5 Hz), 160.68 (d,J_(CF)=4.6 Hz), 146.61, 142.52 (d, J_(CF)=7.4 Hz), 139.04 (d, J_(CF)=6.4Hz), 131.58 (131.63, 131.28, 128.67, 124.25, 123.14, 122.89, 120.56 (d,J_(CF)=21 Hz), 120.05 (d, J_(CF)=21 Hz), 116.52, 115.64, 114.80 (d,J_(CF)=25 Hz), 113.97 (d, J_(CF)=25 Hz), 51.88, 45.82, 44.84, 41.79,12.31; Ms (posES-FIA) m/z=551 (M+H).

Example 2

N-[2-[ethyl(phenylsulfonyl)amino]-4-(4-methyl-1-piperazinyl)phenyl]-benzenesulfonamidehydrochloride (Scheme 1, Method 1)

N-[2-[ethyl(phenylsulfonyl)amino]4-(4-methyl-1-piperazinyl)phenyl]benzenesulfonamidehydrochloride was prepared as described in Scheme 1. Sulfonylation fromN-2-ethyl4-(4-methyl-1-piperazinyl)-1,2-benzenediamine andphenylsulfonyl chloride was performed as described in Method 1.Purification by chromatography (SiO₂, chloroform:methanol:NH₃ 9:1:0.4%)followed by trituration with MeOH gave 68 mg (15% yield) of the freebase which was converted to its HCl-salt. MS (posES-FIA) m/z=found:514.1700, calc: 514.1708; Anal. (C₂₅H₃₀N₄O₄S₂.2HCl) C, H, N.

Example 3

3-Fluoro-N-[2-{[(3-fluorophenyl)suffonyl]amino}-4-(4-methyl-1-piperazinyl)phenyl]benzenesulfonamidehydrochloride (Scheme 3)

Synthesis of 2-Amino-5-(4-methyl-1-piperazinyl)aniline. A mixture of2-nitro-3-chloraniline (4.47 g, 25.9 mmol), methylpiperazine (3.1 g, 31mmol) and K₂CO₃ (5.41 g, 39 mmol) in acetonitrile was stirred at 70° C.for 48 h. The mixture was filtered and purified by column chromatography(SiO₂, CH₂Cl₂/MeOH/Heptane/NH₃ 4:1:5×0.2%) to give 1.6 g of product(unreacted starting material was isolated): ¹H-NMR δ 7.66-7.45 (m, 5H),6.78 (d, 1H), 6.62 (d, 1H), 6.50 (dd, 1H), 3.39-3.35 (m, 4H), 3.02-2.99(m, 4H); MS (posES-FIA) m/z 333.0 (M⁺+H). The product (1.06 g, 4.49mmol) was dissolved in EtOH:THF (4:1). Raney-Ni and hydrazine (1.12 mL,22 mmol) were added. The reaction was stirred at room temperature for 3h until the yellow color disappeared. Filtration through wet Celite pad,followed by removal of the solvent afforded 0.802 g of2-amino-5-(4-methyl-1-piperazinyl)aniline which was used without furtherpurification in the next step. 3-Fluorobenzenesulfonyl chloride (0.133g, 0.68 mmol) was added to a solution of2-amino-5-(4-methyl-1-piperazinyl)aniline (0.141 g, 0.68 mmol) andpyridine (514 mL, 6.39 mmol) in CH₂Cl₂. After 1 h the mixture was washedwith aq NaHCO₃ (10%), dried (MgSO₄) and the solvent was removed.Purification by chromatography (SiO₂, CH₂Cl₂/methanol/heptane, 4:1:5)gave3-fluoro-N-[2-amino-4-(4-methyl-1-piperazinyl)-phenyl]benzenesulfonamide(0.140 g, 57%). MS (posES-FIA) m/z=found: 365.2, calcd: 364.14; Anal.(C₁₇H₂₂ClFN₄O₂S.3H₂O) C, H, N, S. The reaction produced a small amountof bis-sulfonylated compound3-fluoro-N-[2-{[(3-fluorophenyl)sulfonyl]amino}-4-(4-methyl-1-piperazinyl)-phenyl]benzenesulfonamide(0.010 g, 3%). The products were transformed into their HCl-salt beforeanalysis; MS (posES-FIA) m/z=found. 523.5, calcd: 522.12. Anal.(C₂₃H₂₅ClF₂N₄O₄S₂) C, H, N, S.

Example 4

N-{4-(4-methyl-1-piperazinyl)-2-[(8-quinolinylsulfonyl)amino]phenyl}-8-quinolinesulfonamidehydrochloride (Scheme 3)

8-Quinolinesulfonyl chloride (0.185 g, 0.81 mmol) was added to asolution of 2-amino-5-(4-methyl-1-piperazinyl)aniline (0.168 g, 0.81mmol) and pyridine (514 mL, 6.39 mmol) in CH₂Cl₂. After 1 h at roomtemperature the mixture was washed with aq NaHCO₃ (10%), dried (MgSO₄)and the solvent was removed. Purification by chromatography (SiO₂,CH₂Cl₂/MeOH/heptane, 4:1:5) gaveN-2-amino-4-(4-methyl-1-piperazinyl)-]-phenyl-8-quinolinesulfonamide(0.110 g, 35%). MS (posES-FIA) m/z=found: 384.2, calcd 383.48; %); Anal.(C₁₉H₂₂ClN₅O₂S.3H₂O) C, H, N, S and a small amount of thebis-sulfonylatedN-{4-(4-methyl-1-piperazinyl)-2-[(8-quinolinylsulfonyl)amino]phenyl}-8-quinolinesulfonamide(0.070 g, 15%). The product was converted to HCl salt before analysis;MS (posES-FIA) m/z=found: 589.6, calcd: 588.16; Anal.(C₂₉H₂₉ClN₆O₄S₂.2H₂O) C, H, N.

Synthesis According to Scheme 2

Scheme 2, Method 3: General R1=Me

Intermediate 7

Synthesis of N-(5-fluoro-2-nitrophenyl)benzenesulfonamide (Scheme 2,Method 3)

Benzenesulfonamide (3.14 g, 20 mmol) was dissolved in DMF (100 mL) andNaH (60% in oil, 40 mmol, 1.60 g) was added. The reaction was stirreduntil the gas evolution ceased. 2,4-Difluoronitrobenzene (18 mmol, 2.9g, 2 mL) was added and the reaction mixture was stirred over night at35° C. The reaction mixture was poured into HCl (1M aq, 100 mL) andextracted with toluene (25 mL×5). The organic phase was dried (MgSO₄)and concentrated and re-crystallized from EtOH to give a first crop of3.75 g of a yellow solid. A second crop of 0.20 g was collected from theEtOH remains. Yield 3.95 g, 13.3 mmol (74%). MS (posES-FIA) m/z=found:296; Calc: 296,0.

Intermediate 8

Synthesis ofN-[5-(4-methyl-1-piperazinyl)-2-nitrophenyl]benzenesulfonamide (Scheme2, Method 3)

N-(5-fluoro-2-nitrophenyl)benzenesulfonamide (2×0.50 g, 1.688 mmol) wastreated with N-methyl-piperazine (2×4.65 g, 45.6 mmol) and put in twopyrex tubes and sealed. Each tube was put in a LabWell MW-10 microwaveoven for 2 min at 50W. The reaction mixtures were combined and pouredinto 0.5 M NaOH (aq) and extracted with CH₂Cl₂, dried (MgSO₄) andconcentrated to give 0.99 g, (2.63 mmol) in 78% yield as a yellow solid.Anal (C₁₇ H₂₀ N₄ O₄ S) C, H, N, S; MS (posES-FA) m/z=found: 377.4;Calcd: 376.12.

Example 5

N-[2-Chloro-4-({4-(4-methyl-1-piperazinyl)-2-[(phenylsulfonyl)amino]-anilino}sulfonyl)phenyl]acetamidehydrochloride (Scheme 2, Method 3)

N-[5-(4-Methyl-1-piperazinyl)-2-nitrophenyl]benzenesulfonamide (0.600 g,1.59 mmol) was dissolved in THF (20 mL) followed by the addition ofRaney-Ni (0.322 g, in ethanol) and hydrazine hydrate (0.100 g, 2.0mmol). The reaction mixture was stirred for 1 h, filtered through Celiteand concentrated. The residue was dissolved in pyridine (12 mL) anddivided in 12 equal parts. To one part was added3-cloro-4-N-acetamido-benzenesulfonylchloride (52 mg, 0.20 mmol). Thereaction mixture was stirred over night, poured into petroleum ether toform a precipitate that was collected by centrifugation. The precipitatepurified by column chromatography (SiO₂, CH₂Cl₂/MeOH 95:5 to 9:1). Thepure product was dissolved in MeOH and treated with HCl/diethyl ether togive 9.6 mg, (12% yield). MS (posES-FIA) m/z=found: 578.4; Calcd:577.12.

Example 6

3,4-Dimethoxy-N-{4-(4-methyl-1-piperazinyl)-2-[(phenylsulfonyl)-amino]phenyl}benzenesulfonamidehydrochloride (Scheme 2, Method 3)

N-[5-(4-Methyl-1-piperazinyl)-2-nitrophenyl]benzenesulfonamide (0.600 g,1.59 mmol) was dissolved in THF (20 mL) followed by the addition ofRaney-Ni (0.322 g, in ethanol) and hydrazine hydrate (0.100 g, 2.0mmol). The reaction mixture was stirred for 1 h, filtered through Celiteand concentrated. The residue was dissolved in pyridine (12 mL) anddivided in 12 equal parts. To one part was added3,4-dimethoxy-bensenesulfonylchloride (47 mg, 0.20 mmol). The reactionmixture was stirred overnight, poured into petroleum ether to form aprecipitate that was collected by centrifugation. The precipitate waspurified by column chromatography (SiO₂, CH₂Cl₂/MeOH 95:5 to 9:1). Thepure product was dissolved in MeOH and treated with HCl/diethyl ether togive 34.5 mg, (45% yield). MS (posES-FIA) m/z=found: 547.4; Calcd:546.16.

Example 7

3-Methoxy-4-methyl-N-{4-(4-methyl-1-piperazinyl)-2-[(phenylsulfonyl)-amino]phenyl}benzenesulfonamidehydrochloride (Scheme 2, Method 3)

N-[5-(4-Methyl-1-piperazinyl)-2-nitrophenyl]benzenesulfonamide (0.600 g,1.59 mmol) was dissolved in THF (20 mL) followed by the addition ofRaney-Ni (0.322 g, in ethanol) and hydrazine hydrate (0.100 g, 2.0mmol). The reaction mixture was stirred for 1 h, filtered through Celiteand concentrated. The residue was dissolved in pyridine (12 mL) anddivided in 12 equal parts. To one part was added2-methoxy4-methyl-benzenesulfonylchloride (44 mg, 0.20 mmol). Thereaction mixture was stirred overnight, poured into petroleum ether toform a precipitate that was collected by centrifugation. The precipitatewas purified by purified by column chromatography (SiO₂, CH₂C₂/MeOH 95:5to 9:1). The pure product was dissolved in MeOH and treated withHCl/diethyl ether to give 21 mg, (28% yield). MS (posES-FIA) m/z=found:530.1635; Calcd: 530.1658.

Intermediate 9

Synthesis of N-(5-fluoro-2-nitrophenyl)methanesulfonamide (Scheme 2,Method 3)

Methylsulfonamide (2.421 g, 25.4 mmol) was dissolved in DMF (100 mL) andNaH (60% in oil, 1.00 g, 25 mmol) was added. The reaction stirred for 1h and added to a stirred solution of 2,4-difluoronitrobenzene (4.372 g,27.5 mmol) in DMF (20 mL). The reaction mixture was stirred for 2 h,poured into a mixture (1:1) of brine and 1M HCl, and extracted withtoluene. The organic phase was dried (MgSO₄), and concentrated to give asolid that was crystallized from toluene/petroleum ether. The flasktipped over and some material was lost, to give 1.32 g, 5.64 mmol in 22%yield. MS (posES-FIA) m/z=found: 234; Calcd: 234.01; Anal (C₇ H₇ F N₂ O₄S), C, H, N, S.

Intermediate 10

Synthesis ofN-[5-(4-methyl-1-piperazinyl)-2-nitrophenyl]-methanesulfonamide (Scheme2, Method 3).

N-(5-fluoro-2-nitrophenyl)methanesulfonamide (1.33 g, 5.68 mmol) wasdissolved in DMF (10 mL) and N-methylpiperazine (2.00 g, 20 mmol) wasadded. The reaction mixture was stirred at 20° C. for 1 h, and thenheated with a heat gun for 5 min to reach boiling of DMF (150° C.), thenleft stirring for another hour. The reaction mixture was then pouredinto brine and extracted with toluene (10 mL×2), EtOAc (20 mL×2) andCH₂Cl₂ (20 mL×2), NaHCO₃ was then added to the water phase and then thewater phase was extracted with CH₂Cl₂ (20 mL×2). The organic phases werecombined and dried (MgSO₄) and concentrated to give a semi solid. EtOHwas added and left over night and then filtered off to give 1.503 g(4.78 mmol) in 84% yield. MS (posES-FIA) m/z=found: 315; Calc M=314.10;Anal (C₁₂ H₁₈ N₄ O₄ S), C, H, N, S.

Example 8

4-Methyl-N-{4-(4-methyl-1-piperazinyl)-2-[(methylsulfonyl)amino]-phenyl}benzenesulfonamidehydrochloride (Scheme 2, Method 3)

N-[5-(4-methyl-1-piperazinyl)-2-nitrophenyl]-methanesulfonamide (0.45 g,1.43 mmol) was dissolved in THF (10 mL) followed by the addition ofRaney-Ni (0.15 g in ethanol) and hydrazine hydrate (78 mg, 1.56 mmol).The reaction was stirred for 1 h. Another aliquot of hydrazine hydrate(20 μL) was added and the reaction stirred for another hour, filteredthrough Celite and concentrated to give 0.42 g that was used to the nextstep without further purification. The material was dissolved in DMF (10mL) and divided into 3 equal parts. To one part was added p-toluenesulfonyl chloride (0.095 g, 0.5 mmol) and the reaction was stirred for 1h and poured into a mixture of petroleum ether/acetone (30 mL/10 mL) togive a precipitate. Additional product was found in the solution andadded to the precipitate. The product was isolated by chromatography(SiO₂, CH₂Cl₂/MeOH 9:1) to give 0.063 g, ( 28% yield). MS (posES-FIA)m/z=found: 38.1393; Calcd: 438.1395.

Example 9

3,4-Dimethoxy-N-{4-(4-methyl-1-piperazinyl)-2-[(methylsulfonyl)amino]-phenyl}benzenesulfonamidehydrochloride (Scheme 2, Method 3)

N-[5-(4-methyl-1-piperazinyl)-2-nitrophenyl]-methanesulfonamide (0.45 g,1.43 mmol) was dissolved in THF (10 mL) and Raney-Ni (0.15 g in ethanol)was added followed by hydrazine hydrate (78 mg, 1.56 mmol) and thereaction was stirred for 1 h. Additional hydrazine hydrate (20 μL) wasadded and the reaction stirred for another hour, filtered through Celiteand concentrated to give 0.42 g of product that was used without furtherpurification. The material was dissolved in DMF (10 mL) and divided into3 equal parts. To one part was added 3,4dimethoxybensenesulfonylchloride (0.118 g, 0.5 mmol) and the reactionwas stirred for 1 h, poured into a mixture of petroleum ether/acetone(30 mL/10 mL) to form a precipitate. Additional product was found in thesolution and was added to the precipitate. The product was isolated bychromatography (SiO₂, CH₂Cl₂/MeOH 9:1) to give 0.064 g, (26% yield). MS(posES-FIA) m/z=found: 484.1436; Calcd: 484.1450.

Example 10

3-Cyano-N-{4-(4-methyl-1-piperazinyl)-2-[(methylsulfonyl)amino]-phenyl}benzenesulfonamidehydrochloride (Scheme 2, Method 3)

N-[5-(4-methyl-1-piperazinyl)-2-nitrophenyl]-methanesulfonamide (0.45 g,1.43 mmol) was dissolved in THF (10 mL) and Rayney-Ni (0.15 g inethanol) was added followed by hydrazine hydrate (78 mg, 1.56 mmol) andthe reaction was stirred for 1 h. Additional hydrazine hydrate (20 μL)was added and the reaction stirred for another hour, filtered throughCelite and concentrated to give 0.42 g of product that was used withoutfurther purifications. The material was dissolved in DMF (10 mL) anddivided into 3 equal parts. To one part was added3-cyanobenzenesulfonylchloride (0.101 g, 0.5 mmol) and the reaction wasstirred for 1 h. poured into a mixture of petroleum ether/acetone (30mL/10 mL) to form a precipitate. Additional product was found in thesolution and was combined to the precipitate. The product was isolatedby chromatography (SiO₂, CH₂Cl₂/MeOH 9:1) to give 0.0301 g, (13% yield).MS (posES-FIA) m/z=found: 449.1177; Calcd: 449.1191.

Scheme 2, Method 4: General R1=H

N-(2-amino-5-(4-boc-1-piperazinyl)-phenyl)-benzenesulfonamide

A mixture of N-(2-nitro-3-fluorophenyl)-benzenesulfonamide (4.68 g, 15.7mmol), Boc-piperazine (3.5 g, 18.9 mmol) and K₂CO₃ (3.8 g, 27.8 mmol) inDMF was stirred at 70° C. for 24 h. The mixture was filtered andpurified by column chromatography (SiO₂, CH₂Cl₂/MeOH/heptane/NH₃4:1:5:0.2%) to give 2.0 g of desired product. ¹H-NMR δ 7.98 (d, 1H),7.89-7.84 (m, 2H), 7.63-7.50 (m, 3H), 7.00 (d, 1H), 6.68 (dd, 1H),3.59-3.45 (m, 8H), 1.49 (s, 9H); MS (posES-FIA) m/z=found: 485.0(M⁺+Na⁺). The product (1.85 g, 4.00 mmol) was dissolved in EtOH:THF(4:1) followed by addition of Raney-Ni and hydrazine (1.0 mL, 20 mmol).The reaction was stirred at room temperature for 3 h until the yellowcolor disappeared. Filtration through wet Celite, followed by removal ofthe solvent afforded 1.26 g ofN-(2-amino-5-(4-tert-butoxycarbonyl-1-piperazinyl)-phenyl)-benzenesulfonamidewhich was used without further purification.

To a solution ofN-{2-amino-5-(4-t-butyloxycarbonyl-piperazinyl)-phenyl}benzenesulfonamide(79 mg, 0.184 mmol) and pyridine (131 μL, 1.6 mmol) in CH₂Cl₂ (7 mL) anddifferent sulfonylchlorides (0.239 mmol) was added. After 2 h at roomtemperature the solvent was removed. Purification by chromatography(SiO₂, CH₂Cl₂/MeOH/heptane, 4:1:15) followed by Boc-deprotection whichwas achieved by dissolving the residue in small amount of MeOH andadding HCl/ether. The mixture was left at room temperature for 0.5 hafter which the solvent was removed. Re-crystallization (MeOH/ether)afforded the final products respectively.

Example 11

N-{4-(1-Piperazinyl)-2-[(phenylsulfonyl)amino]phenyl}-1-naphthalenesulfonamidehydrochloride (Scheme 2, Method 4)

N-{4-(1-Piperazinyl)-2-[(phenylsulfonyl)amino]phenyl}-1-naphthalenesulfonamidewas synthesized fromN-{2-amino-5-(4-t-butyloxycarbonyl-piperazinyl)-phenyl}benzenesulfonamideand 1-naphthalenesulfonylchloride (54 mg, 0.239 mmol) according togeneral method 3 to give 40 mg of a purple solid. MS (posES-FIA)m/z=Found: 523.2; Calcd 523.14; ¹H NMR δ 8.83-8.59 (m, 1H), 8.10 (d,1H), 8.02-7.97 (m, 1H), 7.90 (d, 1H), 7.74-7.38 (m, 8H), 6.69-6.65 (m,1H), 6.39-6.34 (m, 2H), 3.35-3.14 (m, 8H).

Example 12

5-(Dimethylamino)-N-{4-(1-piperazinyl)-2-[(phenylsulfonyl)amino]phenyl}-1-naphthalenesulfonamidehydrochloride (Scheme 2, Method 4)

5-(Dimethylamino)-N-{4-(1-piperazinyl)-2-[(phenylsulfonyl)amino]phenyl}-1-naphthalenesulfonamidewas synthesized fromN-{2-amino-5-(4-t-butyloxycarbonyl-piperazinyl)-phenyl}benzenesulfonamideand dansylchloride (64 mg, 0.239 mmol) according to general method 3 togive 60 mg of a purple solid. MS (posES-FIA) m/z=Found: 566.3; Calcd:566.18; ¹H NMR δ 8.84 (d, 1H), 8.60 (d, 1H), 8.08 (d, 2H), 7.84-7.47 (m,7H), 6.70 (d, 1H), 6.56-6.53 (m, 1H), 6.41-6.37 (m, 1H), 3.46 (s, 6H),3.25-3.12 (m, 8H).

Example 13

N-[2-[(Phenylsulfonyl)amino]-4-(1-piperazinyl)phenyl]-8-quinolinesulfonamidehydrochloride (Scheme 2, Method 4)

N-[2-[(Phenylsulfonyl)amino]-4-(1-piperazinyl)phenyl]-8-quinolinesulfonamidewas synthesized fromN-{2-amino-5-(4-t-butyloxycarbonyl-piperazinyl)-phenyl}benzenesulfonamideand 8-quinolinesulfonylchloride (54 mg, 0.239 mmol) according to generalmethod 3 to give 50 mg of a purple solid. MS (posES-FIA) m/z=Found:524.2; Calcd: 524.13; ¹H NMR δ 9.34 (dd, 1H), 8.79 (dd, 1H), 8.37 (dd,1H), 8.25 (dd, 1H), 7.92 (dd, 1H), 7.73 (t, 1H), 7.57-7.40 (m, 5H), 7.17(d, 1H), 6.71 (dd, 1H), 6.14 (d, 1H), 3.23-3.08 (m, 8H).

Example 14

2,4,6-Trimethyl-N-[2-[(phenylsulfonyl)amino]-4-(1-piperazinyl)phenyl]benzenesulfonamidehydrochloride (Scheme 2, Method 4)

2,4,6-Trimethyl-N-[2-[(phenylsulfonyl)amino]4-(1-piperazinyl)phenyl]benzenesulfonamidewas synthesized fromN-{2-amino-5-(4-t-butyloxycarbonyl-piperazinyl)-phenyl}benzenesulfonamideand 2-mesitylenesulfonylchloride (52 mg, 0.239 mmol) according togeneral method 3 to give 50 mg of a purple solid. MS (posES-FIA)m/z=Found: 515.3; Calcd 515.17; ¹H-NMR δ 7.74 (d, 2H); 7.63-7.46 (m,3H), 6.92 (s, 2H), 6.74-6.55 (m, 3H), 3.27-3.20 (m, 8H), 2.35 (s, 6H),2.25 (s, 3H).

Example 15

4-Methyl-N-[2-[(phenylsulfonyl)amino]-4-(1-piperazinyl)phenyl]benzenesulfonamidehydrochloride (Scheme 2, Method 4)

4-Methyl-N-[2-[(phenylsulfonyl)amino]-4-(1-piperazinyl)phenyl]benzenesulfonamidewas synthesized fromN-{2-amino-5-(4-t-butyloxycarbonyl-piperazinyl)-phenyl}benzenesulfonamideand p-toluenesulfonylchloride (46 mg, 0.239 mmol) according to generalmethod 3 to give 70 mg of a purple solid. MS (posES-FIA) m/z=Found:487.2; Calcd: 487.14; ¹H-NMR δ 7.73-7.45 (m, 7H), 7.26 (d, 2H), 6.74 (s,1H), 6.62-6.60 (m, 2H), 3.69 (app t, 2H), 3.39 (app t, 2H), 3.29-3.74(m, 4H), 2.38 (s, 3H).

Example 16

N-[2-({[(E)-2-Phenylethenyl]sulfonyl}amino)-5-(1-piperazinyl)phenyl]benzenesulfonamidehydrochloride (Scheme 2, Method 4)

N-[2-({[(E)-2-Phenylethenyl]sulfonyl}amino)-5-(1-piperazinyl)phenyl]benzenesulfonamidewas synthesized fromN-{2-amino-5-(4-t-butyloxycarbonyl-piperazinyl)-phenyl}benzenesulfonamideand β-styrenesulfonylchloride (48 mg, 0.239 mmol according to generalmethod 3 to give before Boc-deprotection 160 mg of a purple solid. MS(posES-FIA) m/z=Found: 499.2; Calcd 499.14; ¹H-NMR δ 8.26 (d, 1H), 8.04(d, 1H), 7.75-7.38 (m, 8H), 7.22 (d, 1H, J=15.4 Hz), 7.16 (d, 1H), 6.97(d, 1H), J=15.4 Hz), 6.78 (dd, 1H), 6.68 (d, 1H), 3.68 (app t, 2H), 3.39(app t, 2H), 3.28-3.21 (m, 4H).

Example 17

2,5-Dimethoxy-N-[2-[(phenylsulfonyl)amino]-4-(1-piperazinyl)phenyl]benzenesulfonamidehydrochloride (Scheme 2, Method 4)

2,5-Dimethoxy-N-[2-[(phenylsulfonyl)amino]4-(1-piperazinyl)phenyl]benzenesulfonamidewas synthesized from ofN-{2-amino-5-(4-t-butyloxycarbonyl-piperazinyl)-phenyl}benzenesulfonamideand 2,5-dimethoxybenzenesulfonylchloride (57 mg, 0.239 mmol) accordingto general method 3 to give 60 mg of a purple solid. MS (posES-FIA)m/z=Found: 533.1; Calcd: 533.14; ¹H-NMR δ 7.68-7.48 (m, 5H), 7.16-7.05(m, 4H), 6.69 (dd, 1H), 6.42 (d, 1H), 4.03 (s, 3H), 3.69 (s, 3H),3.26-3.10 (m, 8H).

Example 18

2-Methyl-N-[2-[(phenylsulfonyl)amino]-4-(1-piperazinyl)phenyl]benzenesulfonamidehydrochloride (Scheme 2, Method 4)

2-Methyl-N-[2-[(phenylsulfonyl)amino]-4-(1-piperazinyl)phenyl]benzenesulfonamidewas synthesized fromN-{2-amino-5-(4-t-butyloxycarbonyl-piperazinyl)-phenyl}benzenesulfonamideand o-toluenesulfonylchloride (46 mg, 0.239 mmol) according to generalmethod 3 to give before Boc-deprotection 160 mg of a purple solid. MS(posES-FIA) m/z=Found: 487.1; Calcd 487.14; ¹H-NMR δ 7.74-7.16 (m, 8H),6.78-6.52 (m, 4H), 3.27-3.16 (m, 8H), 2.58 (s, 3H).

Example 19

2,4-Difluoro-N-[2-[(phenylsulfonyl)amino]-4-(1-piperazinyl)phenyl]benzenesulfonamidehydrochloride (Scheme 2, Method 4)

2,4-Difluoro-N-[2-[(phenylsulfonyl)amino]-4-(1-piperazinyl)phenyl]benzenesulfonamidewas synthesized fromN-{2-amino-5-(4-t-butyloxycarbonyl-piperazinyl)-phenyl}benzenesulfonamideand 2,4-difluorobenzenesulfonylchloride (94 mg, 0.455 mmol) according togeneral method 3 to give before Boc-deprotection 160 mg of a purplesolid. MS (posES-FIA) m/z=Found: 509.1; Calcd 509.11; ¹H-NMR δ77.71-7.46 (m, 6H), 7.25-7.17 (m, 1H), 7.03-6.96 (m, 2H), 6.72 (dd, 1H),6.44 (d, 1H), 3.20-3.16 (m, 8H).

Example 20

4-Butoxy-N-[2-[(phenylsulfonyl)amino]-4-(1-piperazinyl)phenyl]benzenesulfonamidehydrochloride (Scheme 2, Method 4)

4-Butoxy-N-[2-[(phenylsulfonyl)amino]4-(1-piperazinyl)phenyl]benzenesulfonamidewas synthesized fromN-{2-amino-5-(4-t-butyloxycarbonyl-piperazinyl)-phenyl}benzenesulfonamideand 4-n-butoxybenzenesulfonylchloride (59 mg, 0.239 mmol) according togeneral method 3 to give 70 mg of a purple solid. MS (posES-FIA) m/z=Found: 545.2; Calcd 545.18; ¹H-NMR δ 7.73-7.45 (m, 7H), 6.95-6.91 (m,2H), 6.72-6.70 (m, 1H), 4.00 (t, 2H), 3.29-3.24 (m, 8H), 1.79-1.70 (m,2H), 1.55-1.43 (m, 2H), 0.97 (t, 3H).

Example 21

3,5-Dimethyl-N-[2-[(phenylsulfonyl)amino]-4-(1-piperazinyl)phenyl]-4-isoxazolesulfonamidehydrochloride (Scheme 2, Method 4)

3,5-Dimethyl-N-[2-[(phenylsulfonyl)amino]-4-(1-piperazinyl)phenyl]-4-isoxazolesulfonamidewas synthesized fromN-{2-amino-5-(4-t-butyloxycarbonyl-piperazinyl)-phenyl}benzenesulfonamideand 3,5-dimethylisoxazolesulfonylchloride (47 mg, 0.239 mmol) accordingto general method 3 to give 70 mg of a purple solid. MS (posES-FIA)m/z=Found: 492.1; Calcd 492.13; ¹H-NMR δ 7.72-7.47 (m, 5H), 6.98 (d,1H), 6.80 (dd, 1H), 6.50 (d, 1H), 3.28-3.22 (m, 8H), 2.22 (s, 3H), 2.11(s, 3H).

Example 22

5-Fluoro-2-methyl-N-[2-[(phenylsulfonyl)amino]-4-(1-piperazinyl)phenyl]benzene-sulfonamide(Scheme 2, Method 4)

5-Fluoro-2-methyl-N-[2-[(phenylsulfonyl)amino]-4-(1-piperazinyl)-phenyl]benzenesulfonamidewas synthesized fromN-{2-amino-5-(4-t-butyloxycarbonyl-piperazinyl)-phenyl}benzenesulfonamideand 5-fluoro-2-methylbenzenesulfonylchloride (50 mg, 0.239 mmol)according to general method 3 to give 60 mg of a purple solid. MS(posES-FIA) m/z=Found: 505.2; Calcd 505.13; ¹H-NMR δ 7.73-7.17 (m, 8H),6.83 (d, 1H), 6.68 (dd, 1H), 6.50 (dd, 1H), 3.27-3.17 (m, 8H), 2.55 (s,3H).

Example 23

4-(Methylsulfonyl)-N-[2-[(phenylsulfonyl)amino]-4-(1-piperazinyl)phenyl]-benzenesulfonamidehydrochloride (Scheme 2, Method 4)

4-(Methylsulfonyl)-N-[2-[(phenylsulfonyl)amino]4-(1-piperazinyl)-phenyl]benzenesulfonamidewas synthesized fromN-{2-amino-5-(4-t-butyloxycarbonyl-piperazinyl)-phenyl}benzenesulfonamideand 4-methylsulfonylbenzenesulfonylchloride (61 mg, 0.455 mmol)according to general method 3 to give 70 mg of a purple solid. MS(posES-FIA) m/z=Found: 551.2; Calcd: 551.10.

Example 24

2-(Methylsulfonyl)-N-[2-[(phenylsulfonyl)amino]-4-(1-piperazinyl)phenyl]benzenesulfonamidehydrochloride (Scheme 2, Method 4)

2-(Methylsulfonyl)-N-[2-[(phenylsulfonyl)amino]-4-(1-piperazinyl)phenyl]benzenesulfonamidewas synthesized fromN-{2-amino-5-(4-t-butyloxycarbonyl-piperazinyl)-phenyl}benzenesulfonamideand 2-methylsulfonylbenzenesulfonylchloride (61 mg, 0.239 mmol)according to general method 3 to give 70 mg of a purple solid. MS(posES-FIA) m/z=Found: 551.2; Calcd: 551.10; ¹H-NMR δ 8.36-7.46 (m, 9H),6.95 (d, 1H), 6.68 (dd, 1H), 6.46 (d, 1H), 3.47 (s, 3H), 3.28-3.17 (m,8H).

Example 25

2-Methoxy-4-methyl-N-[2-[(phenylsulfonyl)amino]-4-(1-piperazinyl)phenyl]benzenesulfonamidehydrochloride (Scheme 2, Method 4)

2-Methoxy-4-methyl-N-[2-[(phenylsulfonyl)amino]-4-(1-piperazinyl)phenyl]benzenesulfonamidewas synthesized fromN-{2-amino-5-(4-t-butyloxycarbonyl-piperazinyl)-phenyl}benzenesulfonamideand 2-methoxy-4-methylbenzenesulfonylchloride (53 mg, 0.239 mmol)according to general method 3 to give 80 mg of a purple solid. MS(posES-FIA) m/z=Found: 517.2; Calcd 517.15; ¹H NMR δ 7.67-7.37 (m, 6H),7.10-7.04 (m, 2H), 6.97-6.74 (m, 2H), 6.30 (d, 1H), 4.06 (s, 3H),3.26-3.09 (m, 8H), 2.37 (s, 3H).

Example 26

4-Methoxy-2-methyl-N-[2-[(phenylsulfonyl)amino]-4-(1-piperazinyl)phenyl]benzenesulfonamidehydrochloride (Scheme 2, Method 4)

4-Methoxy-2-methyl-N-[2-[(phenylsulfonyl)amino]-4-(1-piperazinyl)phenyl]benzenesulfonamidewas synthesized fromN-{2-amino-5-(4-t-butyloxycarbonyl-piperazinyl)-phenyl}benzenesulfonamideand 2-methyl-4-trifluoromethoxybenzenesulfonylchloride (53 mg, 0.455mmol) according to general method 3 to give before Boc-deprotection 70mg of a purple solid. MS (posES-FIA) m/z=Found: 571.2; Calcd 571.12; ¹HNMR δ 773-7.09 (m, 8H), 6.86 (d, 1H), 6.69 (dd, 1H), 6.48 (d, 1H),3.29-3.17 (m, 8H), 2.62 (s, 3H).

Example 27

N-{4-(homopiperazinyl)-2-[(phenylsulfonyl)amino]phenyl}benzenesulfonamidehydrochloride (Scheme 1, Method 2)

Benzenesulfonyl chloride (0.088 g, 0.50 mmol) was added to a solution of2-amino-5-(4-t-butyloxycarbonyl-homopiperazin-1-yl)aniline (0.153 g,0.50 mmol) and pyridine (514 mL, 6.39 mmol) in DCM. After 1 h at r.t.the mixture was washed with NaHCO₃ (10%) dried (MgSO₄) and the solventwas removed. Purification by column chromatography (CH₂Cl₂/MeOH/heptane,4:1:15) gave a mixture ofN-{2-amino-4-[4-t-butyloxycarbonyl-homopiperazin-1-yl-]phenyl}benzenesulfonamideand of the bis-sulphonylatedN-{4-[4-t-butyloxycarbonyl]homopiperazinyl)-2-[(phenylsulfonyl)amino]phenyl}benzenesulfonamide(0.150 g, 86%). Boc-deprotection was achieved by dissolving the mixturein MeOH and adding HCl/ether. The mixture was let at r.t. for 0.5 h.Purification by preparative HPLC gaveN-{4-(homopiperazinyl)-2-[(phenylsulfonyl)amino]phenyl}benzenesulfonamidehydrochloride; Anal. (C₂₃H₂₇ClN₄O₄S₂) C, H, N, S; M+487.4 Calcd 486.14.AndN-{4-(homopiperazinyl)-2-[(phenylsulfonyl)amino]phenyl}benzenesulfonamidehydrochloride; Anal. (C₁₇H₂₃ClN₄O₂S) C, H, N, S ; M+347.5 Calcd 346.15.

Example 28

N-(4-(1,4-diazepan-1-yl)-2-{[(3-fluorophenyl)sulfonyl]amino}phenyl)-3-fluorobenzenesulfonamidehydrochloride (Scheme 1, Method 2)

The compound was prepared from2-amino-5-(4-t-butyloxycarbonyl-1-homopiperazinyl)aniline and3-flourobenzenesulfonyl chloride. Purification by column chromatography(CH₂Cl₂/MeOH/heptane, 4:1:15) gave a mixture ofN-{2-amino-4-[4-t-butyloxycarbonyl-homopiperazin-1-yl-]phenyl}3-fluorobenzenesulfonamideandN-{4-[4-t-butyloxycarbonyl]homopiperazinyl)-2-[(3-flourophenylsulfonyl)amino]phenyl}-3-fluorobenzenesulfonamide(0.180 g, 73%). Boc-deprotection was achieved by dissolving the mixturein small amount of MeOH and adding HCl/ether. The mixture was let atr.t. for 0.5 h. Purification by preparative HPLC gaveN-(4-(1,4-diazepan-1-yl)-2-{[(3-fluorophenyl)sulfonyl}phenyl)-3-fluorobenzenesulfonamidehydrochloride Anal. (C₂₃H₂₇ClN₄O₄S₂) C, H, N, S.; M+524.4 Calcd 522.12.

Example 29

N-{4-(1,4-diazepan-1-yl)-2-[ethyl(phenylsulfonyl)amino]phenyl}benzenesulfonamidehydrochloride (Scheme 1, Method 2)

A solution of benzenesulfonyl chloride (0.579 mL, 4.53 mmol) in DCM (2.0mL) was added to tert-butyl4-[4-amino-3-(ethylamino)phenyl]-1,4-diazepane-1-carboxylate (0.605 g,1.81 mmol), and pyridine (1.02 mL, 12.67 mmol) in DCM (8.0 mL). Themixture was stirred at room temperature for 16 hours and thenconcentrated. The crude intermediate was purified by columnchromatography on silica using CHCl₃/10% MeOH+0.4% NH₃. Deprotectionusing HCl-ether/EtOAc gave 0.365 g of the crude product as a HCl-salt.Purification on a reversed phase preperative HPLC gave 94 mg of theproduct as an acetic acid salt which was converted to the HCl salt andrecrystallized from MeOH/Ether: yield 64 mg. ¹H NMR (DMSO-d6) δ 9.05 (brs, 2H), 8.66 (s, 1H), 7.89-7.85 (m, 2H), 7.75-7.55 (m, 8H), 7.07 (app d,J=9.1 Hz, 1H), 6.71-6.66 (m, 1H), 5.70 (app d, J=3.2 Hz, 1H), 3.50-3.32(m, partly obscured by HDO signal, 4H), 3.18-3.14 (m, 2H), 3.05-2.90 (m,2H), 1.90-1.81 (m, 2H), 0.67 (tr, J=7.2 Hz, 3H); Ms (posES-FIA) m/z515(M+H)

Method 4 (Scheme 2)

Diverse sulfonylchlorides were added to a solution ofN-{2-amino-5-(4-t-butyloxycarbonyl-1,4-diazepan-1-yl)-phenyl}benzenesulfonamide and pyridine (135 μL, 1.7 mmol) in DCM (7mL),.After 1 h at r.t. the solvent was removed. Purification by columnchromatography (CH₂Cl₂/MeOH/Heptane, 4:1:15) followed byBoc-deprotection which was achieved by dissolving the residue in smallamount of MeOH and adding HCl/ether. The mixture was left at r.t. for0.5 h after which the solvent was removed. Recrystallization(MeOH/ether) afforded the final product.

Example 30

N-{5-(1,4-diazepan-1-yl)-2-[(methylsulfonyl)amino]phenyl}benzenesulfonamide(Scheme 2, Method 4)

N-{5-(1,4-diazepan-1-yl)-2-[(methylsulfonyl)amino]phenyl}benzenesulfonamidewas synthesized fromN-{2-amino-5-(4-t-butyloxycarbonyl-1,4-diazepan-1-yl)-phenyl}benzenesulfonamide(0.075 g, 0.16 mmol) and, methanesulfonyl chloride (0.017 mL, 0.22mmole) to give 41.6 mg of a light purple solid; Anal.(C₂₄H₂₇ClN₄O₃S×1.3H₂O H, N, S.; M+425.4 Calcd 425.12.

Example 31

N-{5-(1,4-diazepan-1-yl)-2-[(ethylsulfonyl)amino]phenyl}benzenesulfonamidehydrochloride (Scheme 2, Method 4)

N-{5-(1,4-diazepan-1-yl)-2-[(ethylsulfonyl)amino]phenyl}benzenesulfonamidehydrochloride was synthesized fromN-{2-amino-5-(4-t-butyloxycarbonyl-1,4-diazepan-1-yl)-phenyl}benzenesulfonamide(0.085 g, 0.19 mmol) and ethanesulfonyl chloride (0.032 μL, 0.25 mmol)to give 29.1 mg of a light purple solid; Anal. (C₂₄H₂₇ClN₄O₃S×0.75H₂O)C, H, N, S.; M+439.4 Calcd 439.14.

Example 32

N-{4-(1,4-diazepan-1-yl)-2-[(phenylsulfonyl)amino]phenyl}[1,1′-biphenyl]-4-sulfonamidehydrochloride (Scheme 2, Method 4)

N-{4-(1,4-diazepan-1-yl)-2-[(phenylsulfonyl)amino]phenyl}[1,1′-biphenyl]-4-sulfonamidehydrochloride was synthesized fromN-{2-amino-5-(4-t-butyloxycarbonyl-1,4-diazepan-1-yl)-phenyl}benzenesulfonamide (0.081 g, 0.18 mmol) and,1,1′-biphenyl-4-sulfonyl chloride (0.059 g, 0.24 mmol) to give 42.9 mgof a light purple solid; Anal. (C₂₄H₂₇ClN₄O₃S) C, H, N, S.; M+563.5Calcd 563.17.

Example 33

N-(2,1,3-benzoxadiazol-4-yl)-4-(1,4-diazepan-1-yl)-2-[(phenylsulfonyl)amino]benzenesulfonamidehydrochloride (Scheme 2, Method 4)

N-(2,1,3-benzoxadiazol4-yl)-4-(1,4-diazepan-1-yl)-2-[(phenylsulfonyl)amino]benzenesulfonamidehydrochloride was synthesized fromN-{2-amino-5-(4-t-butyloxycarbonyl-1,4-diazepan-1-yl)-phenyl}benzenesulfonamide (0.072 g, 0.16 mmol) and2,1,3-benzoxadiazol-4-yl sulfonyl chloride (0.072 g, 0.21 mmol) to give38.0 mg of a light purple solid; M+1 537.2 Calcd 537.15; ¹HNMR δ 8.21(d, 1H), 7.80 (d, 1H), 7.68-7.46 (m, 6H), 6.92 (d, 1H), 6.49 (dd, 1H),6.12 (d, 1H), 3.57 (app t, 2H), 3.34 (app t, 2H), 3.17 (app t, 2H), 3.11(app t, 2H), 2.03-1.95 (m, 2H).

Example 34

N-{4-(1,4-diazepan-1-yl)-2-[(phenylsulfonyl)amino]phenyl}-2-naphthalenesulfonamidehydrochloride (Scheme 2, Method 4)

N-{4-(1,4-diazepan-1-yl)-2-[(phenylsulfonyl)amino]phenyl}-2-naphthalenesulfonamidehydrochloride was synthesized fromN-{2-amino-5-(4-t-butyloxycarbonyl-1,4-diazepan-1-yl)-phenyl}benzenesulfonamide (0.084 g, 0.19 mmol) and , 2-naphtylsulfonylchloride (0.055 mL, 0.24 mmol) to give 67.8 mg of a light purple solid;Anal. (C₂₄H₂₇ClN₄O₃S) C, H, N, S; M+529.2 Calcd 529.12.

Example 35

N-{4-(1,4-diazepan-1-yl)-2-[(methylsulfonyl)amino]phenyl}benzenesulfonamidehydrochloride (Scheme 2, Method 4)

Benzenesulfonylchloride (0.233 g, 1.8 mmol) was added to a solution ofN-{5-(4-t-butyloxycarbonyl-1,4-diazepan-1-yl)-2-amino]phenyl}methanesulfonamide(0.540 g, 1.4 mmol) and pyridine (0.995 mL, 12.6 mmol) in DCM (40 mL)After 2 h at rt the solvent was removed. Purification by columnchromatography (DCM/MeOH/heptane 4:1:5) gave 580 mg (79%) of a lightpurple solid. Boc-deprotection was carried out by dissolving thecompound in small amount of MeOH and adding HCl/ether. The solvent wasremoved and the product was recrystrallized from MeOH/ether. M+1 425.2Calcd 425.12

Example 36

N-{4-(1,4-diazepan-1-yl)-2-[methyl(methylsulfonyl)amino]phenyl}benzenesulfonamidehydrochloride (Scheme 2, Method 4)

MeI (45 μL, 0.72 mmol) was added to a mixture ofN-{4-(4-t-butyloxycarbonyl-1,4-diazepan-1-yl)-2-[(methylsulfonyl)amino]phenyl}benzenesulfonamide(0.189 g, 0.36 mmol) and K₂CO₃ (0.124, 0.90 mmol) in acetone (25 mL).The mixture was stirred at r.t. for 2 h, filtered and the solvent wasremoved. Columnchromatography (DCM/MeOH/Heptane 4:1:15) gave 110 mg ofN-{4-(4-t-butyloxycarbonyl1,4-diazepan-1-yl)-2-[methyl(methylsulfonyl)amino]-phenyl}benzenesulfonamideand 20 mg of N-{4-(4-t-butyloxycarbonyl1,4-diazepan-1-yl)-2-[(methylsulfonyl)amino]phenyl}-N-methyl-benzenesulfonamide.Boc-deprotection was carried out by dissolving the compounds in smallamount of MeOH and adding HCl/ether. The solvent was removed and theproducts were recrystrallized from MeOH/ether.N-{4-(1,4-diazepan-1-yl)-2-[methyl(methylsulfonyl)amino]phenyl}benzenesulfonamidehydrochloride M+1 439.2 Calcd 439.14.

Example 37

N-{4-(1,4-diazepan-1-yl)-2-[(methylsulfonyl)amino]phenyl}-N-methylbenzenesulfonamidehydrochloride (Scheme 2, Method 4)

MeI (45 μL, 0.72 mmol) was added to a mixture ofN-{4-(4-t-butyloxycarbonyl-1,4-diazepan-1-yl)-2-[(methylsulfonyl)amino]phenyl}benzenesulfonamide(0.189 g, 0.36 mmol) and K₂CO₃ (0.124, 0.90 mmol) in acetone (25 mL).The mixture was stirred at r.t. for 2 h, filtered and the solvent wasremoved. Purification by column chromatography (DCM/MeOH/Heptane 4:1:15)gave 110 mg ofN-{4-(4-t-butyloxycarbonyl1,4-diazepan-1-yl)-2-[methyl(methylsulfonyl)amino]phenyl}benzenesulfonamideand 20 mg of N-{4-(4-t-butyloxycarbonyl1,4-diazepan-1-yl)-2-[(methylsulfonyl)amino]phenyl}-N-methylbenzenesulfonamide. Boc-deprotection was carried out by dissolving thecompounds in small amount of MeOH and adding HCl/ether. The solvent wasremoved and the products were recrystrallized from MeOH/ether.N-{4-(1,4-diazepan-1-yl)-2-[(methylsulfonyl)amino]-phenyl}-N-methylbenzenesulfonamidehydrochloride M+1 439.2 Calcd 439.14.

Example 38

N-{4-(1,4-diazepan-1-yl)-2-[methyl(phenylsulfonyl)amino]phenyl}benzenesulfonamidehydrochloride (Scheme 2, Method 4)

MeI (45 μL, 0.72 mmol) was added to a mixture ofN-{4-(4-t-butyloxycarbonyl-1,4-diazepan-1-yl)-2-[(phenylsulfonyl)amino]phenyl}benzenesulfonamide(0.189 g, 0.36 mmol) and K₂CO₃ (0.124, 0.90 mmol) in acetone (25 mL).The mixture was stirred at r.t. for 2 h, filtered and the solvent wasremoved. Purification by column chromatography (DCM/MeOH/heptane 4:1:15)gaveN-{4-(4-t-butyloxycarbonyl-1,4-diazepan-1-yl)-2-[methyl(phenylsulfonyl)-amino]phenyl}benzenesulfonamideas a colourless oil. Boc-deprotection was carried out by dissolving thecompound in small amount of MeOH and adding HCl/ether. The solvent wasremoved and the residue was recrystrallized from MeOH/ether to give 62.7mg of product M+1 501.3 Calcd 501.16.

Scheme 3

To a solution of N-{2-amino-5-(4-t-butyloxycarbonyl-1,4-diazepan-1-yl)-phenyl}methanesulfonamide (134 mg, 0.35 mmol) and pyridine (250 μL, 3.14mmole) in DCM (7mL), the sulfonylchloride (0.455 mmol) was added. After2 h at r.t. the solvent was removed. Purification by columnchromatography (CH₂Cl₂/MeOH/Heptane, 4:1:15) followed byBoc-deprotection which was achieved by dissolving the residue in smallamount of MeOH and adding HCl/ether. The mixture was left at r.t. for0.5 h after which the solvent was removed. Recrystallization(MeOH/ether) afforded the final product.

Example 39

N-{4-(1,4-diazepan-1-yl)-2-[(methylsulfonyl)amino[phenyl}-1-naphthalenesul-fonamidehydrochloride (Scheme 3)

The compound was synthesized fromN-{2-amino-5-(4-t-butyloxycarbonyl-1,4-diazepan-1-yl)-phenyl}methanesulfonamide and 1-napthalenesufonylchloride (103 mg, 0.455mmol) to give before Boc-deprotection 150 mg of a purple solid. M+1475.1 Calcd 474.14.

Example 40

N-{4-(1,4-diazepan-1-yl)-2-[(methylsulfonyl)amino]phenyl}-2-naphthalenesul-fonamidehydrochloride (Scheme 3)

The compound was synthesized fromN-{2-amino-5-(4-t-butyloxycarbonyl-1,4-diazepan-1-yl)-phenyl}methanesulfonamide and 2-napthalenesufonylchloride (103 mg, 0.455mmol) to give before Boc-deprotection 120 mg of a purple solid. M+1475.1 Calcd 474.14.

Example 41

N-{4-(1,4-diazepan-1-yl)-2-[(methylsulfonyl)amino]phenyl}-4-fluorobenzenesul-fonamidehydrochloride (Scheme 3)

The compound was synthesized fromN-{2-amino-5-(4-t-butyloxycarbonyl-1,4-diazepan-1-yl)-phenyl}methanesulfonamide and 4-fluorobenzenesulfonylchloride (89 mg,0.455 mmol) to give before Boc-deprotection 170 mg of a purple solid.M+1 443.1 Calcd 443.11.

Example 42

N-{4-(1,4-diazepan-1-yl)-2-[(methylsulfonyl)amino]phenyl}-4-nitrobenzenesulfonamidehydrochloride (Scheme 3)

The compound was synthesized fromN-{2-amino-5-(4-t-butyloxycarbonyl-1,4-diazepan-1-yl)-phenyl}methanesulfonamide and 4-nitrobenzenesulfonylchloride (101 mg,0.455 mmol) according to general method 3 to give beforeBoc-deprotection 118 mg of a purple solid. M+1 470.1 Calcd 470.11.

Example 43

N-{4-(1,4-diazepan-1-yl)-2-[(methylsulfonyl)amino]phenyl}-3-(trifluoromethyl)-benzenesulfonamidehydrochloride (Scheme 3)

The compound was synthesized fromN-{2-amino-5-(4-t-butyloxycarbonyl-1,4-diazepan-1-yl)-phenyl}methanesulfonamide and 3-trifluoromethylbenzenesulfonylchloride(111 mg, 0.455 mmol) to give before Boc-deprotection 145 mg of a purplesolid. M+1 493.1 Calcd 493.11.

Example 44

N-{4-(1,4-diazepan-1-yl)-2-[(methylsulfonyl)amino]phenyl}-2-methylbenzenesul-fonamidehydrochloride (Scheme 3)

The compound was synthesized fromN-{2-amino-5-(4-t-butyloxycarbonyl-1,4-diazepan-1-yl)-phenyl}methanesulfonamide and o-toluenesulfonylchloride (87 mg, 0.455mmol) to give before Boc-deprotection 175 mg of a purple solid. M+1439.2 Calcd 438.14.

Example 45

N-{4-(1,4-diazepan-1-yl)-2-[(methylsulfonyl)amino]phenyl}-4-(trifluoromethoxy)-benzenesulfonamidehydrochloride (Scheme 3)

The compound was synthesized fromN-{2-amino-5-(4-t-butyloxycarbonyl-1,4-diazepan-1-yl)-phenyl}methanesulfonamide and 4-trifluoromethoxybenzenesulfonylchloride(119 mg, 0.455 mmol) give 140 mg as a purple solid. M+1 509.1 Calcd509.11.

Example 46

N-{4-(1,4-diazepan-1-yl)-2-[(methylsulfonyl)amino]phenyl}-3,5-dimethyl-4-isoxazolesulfonamidehydrochloride (Scheme 3)

The compound was synthesized fromN-{2-amino-5-(4-t-butyloxycarbonyl-1,4-diazepan-1-yl)-phenyl}methanesulfonamide and 3,5-dimethylisoxazole-4-sulfonylchloride(89 mg, 0.455 mmol) 3 to give 120 mg of as purple solid. M+1 444.2 Calcd444.13.

Example 47

N-{4-(1,4-diazepan-1-yl)-2-[(methylsulfonyl)amino]phenyl}-3-methoxybenzene-sulfonamidehydrochloride (Scheme 3)

The compound was synthesized fromN-{2-amino-5-(4-t-butyloxycarbonyl-1,4-diazepan-1-yl)-phenyl}methanesulfonamide and 3-methoxybenzenesulfonylchloride (94 mg,0.455 mmol) to give 160 mg as a purple solid. M+1 455.2 Calcd 455.13.

Intermediate 11

tert-Butyl4-{4-{[(4-methylphenyl)sulfonyl]amino}-3-[(methylsulfonyl)amino]phenyl}-1,4-diazepane-1-carboxylate(scheme 2, Method 4)

tert-Butyl4-{4-nitro-3-[(methylsulfonyl)amino]phenyl}-1,4-diazepane-1-carboxylate(1 g, 2.4 mmol) was dissolved in THF (20 mL) and methanol (2 mL). Raneynickel (0.2 g) was added followed by hydrazine hydrate (0.2 mL).Nitrogen was evolved and the mixture stirred for 1 hour. The reactionwas shown to be incomplete by tlc (CH₂Cl₂.MeOH 9:1) so a further 0.1 mLof hydrazine hydrate was added. After a further hour, the reactionmixture was absorbed onto a bed of silica gel and eluted withCH₂Cl₂:MeOH:NH₄OH (9:1:0.01 150 mL). The solvent was removed byevaporation, toluene (100 mL) was added and evaporated to remove anywater and hydrazine. The crude amine (0.9 g) was dissolved inacetonitrile (20 mL). To this solution under nitrogen was addeddimethylaminopyridine (0.32 g) and toluenesulfonyl chloride (0.51 g) andthe mixture stirred for 3 hours. The solution was poured into water (100mL) and extracted with ethyl acetate (30 mL). The organic extract waswashed with water, dried over MgSO₄ and evaporated to give 0.83 g ofcrude product which was purified by flash chromatography (EtOAc:Petrol1:1). Yield 0.53 g (41%) ¹H NMR (400 MHz, CDCl₃) δ 1.38, 1.40 (2s, 9 H),1.91 (m, J=6.11 Hz, 2 H), 2.44 (s, 3 H), 3.03, 3.05 (2s, 3 H), 3.16-3.33(m, 2 H), 3.46-3.57 (m, 6 H), 6.02 (s, 1 H), 6.21 (ab, J=9.03 Hz, 1 H),6.30 (ab, J=9.03 Hz, 1 H), 6.97 (d, J=2.69 Hz, 1 H), 7.27 (ab, J=8.55Hz, 2 H), 7.33, 7.36 (2s, 1 H), 7.57 (ab, J=8.06 Hz, 2 H); MS (ESI+) forC₂₄H₃₄N₄O₆S₂ m/z 561.1800 (M+)³⁰ (Calculated 561.1817).

Example 48

N-{4-(1,4-diazepan-1-yl)-2-[(methylsulfonyl)amino]phenyl}-4-methylbenzenesulfonamidehydrochloride (PHA 516123A)

tert-Butyl4-{4-{[(4-methylphenyl)sulfonyl]amino}-3-[(methylsulfonyl)amino]phenyl}-1,4-diazepane-1-carboxylate(0.5 g) was dissolved in methanol (15 mL). A solution of HCl in ethylacetate (1N, 25 mL) was added and the mixture stirred for 2 hours. Ether(200 mL) was added and the mixture stirred for 3 hours to allow fullprecipitation. The product was collected by filtration, washed withether and dried. Yield 0.43 g (98%) ¹H NMR (400 MHz, DMSO-d₆) δ 2.03 (m,2 H), 2.36 (s, 3 H), 2.9 (s, 3 H), 3.02-3.09 (br m, 2 H), 3.11-3.19 (brm, 2 H), 3.41 (br t, J=7.08 Hz, 2 H), 3.63 (br m, 2 H), 6.46 (d ab,J=2.8 Hz, 8.8 Hz, 1 H), 6.62 (ab, J=8.8 Hz, 1 H), 6.71 (d, J=2.8 Hz, 1H), MS (ESI+) for C₁₉H₂₇N₄O₄S₂ m/z 439.148 (M+H)⁺ (Calculated 439.1474).

Intermediate 12

N-ethyl-N-(5-fluoro-2-nitrophenyl)methanesulfonamide (Scheme 2, Method4)

N-ethyl-methanesulfonamide (Mijs et al. J.Chem.Soc.Chem.Com. 1972 p412)(5 g 40.6 mmol) was added to a suspension of sodium hydride (1.9 g, 55%in mineral oil) in anhydrous DMF (100 mL) under nitrogen. The mixturewas warmed to 55° C. for one hour and 2,4-difluoronitrobenzene (4.4 mL)was added dropwise. The reaction was stirred at 60° C. overnight, pouredinto water (500 mL) and the product extracted into CH₂Cl₂ (5×100 mL).The organic extracts were washed with water, dried over MgSO₄ andevaporated to give an oily product. The remaining DMF was removed bytrituration with petrol. The crude product was purified by flashchromatography (ethyl acetate:petrol 1:1) to yield the desired productwhich was recrystallised from ethanol. Yield 3.5 g (33%). Calculated N %10,68 C % 41,22 S % 12,23 H % 4,23; Found N % 10,68 C % 41,39 S % 12,22H % 4,17.

Intermediate 13

tert-Butyl4-{3-[ethyl(methylsulfonyl)amino]-4-nitrophenyl}-1,4-diazepane-1-carboxylate(Scheme 2, Method 4)

N-Ethyl-N-(5-fluoro-2-nitrophenyl)methanesulfonamide (3.2 g, 12.2 mmol),tert-butyl 1-homopiperazinecarboxylate (2.5 g) and potassium carbonate(2 g) were heated together in DMSO at 50° C. for 5 hours. The solutionwas allowed to cool and poured into 500 mL of water. The solid productwas collected by filtration, washed with water and dried. The productwas purified by flash chromatography (ethyl acetate:petrol 1:1). Yield2.6 g (48%) ¹H NMR (400 MHz, CDCl₃) δ 1.16 (t, J=7.33 Hz, 3 H), 1.39 (s,9 H), 2.0 (br, 2 H), 2.99 (s, 3 H), 3.2 (br, 2 H), 3.54-3.75 (br, 8 H),6.65 (br d, J=9.3 Hz, 1 H), 6.67 (d, J=2.93 Hz, 1 H), 8.1 (d, J=9.3 Hz,1 H); MS (ESI+) for C₁₉H₃₀N₄O₆S m/z 442 (M⁺).

Preparation ofN-{4-(1,4-diazepan-1-yl)-2-[ethyl(methylsulfonyl)amino]phenyl}-sulfonamides

tert-Butyl4-{3-[ethyl(methylsulfonyl)amino]-4-nitrophenyl}-1,4-diazepane-1-carboxylate(2.5 g, 5.7 mmol) was dissolved in THF (50 mL) and methanol (5 mL).Raney nickel (0.5 g) was added followed by hydrazine hydrate (0.5 mL).Nitrogen was evolved and the mixture stirred for 1 hour. The reactionmixture was absorbed onto a bed of silica gel and eluted withCH₂Cl₂:MeOH:NH₄OH (9:1:0.01 200 mL). The solvent was removed byevaporation, toluene (200 mL) was added and evaporated to remove anywater and hydrazine. The crude amine (2.15 g) was dissolved inacetonitrile (50 mL) with dimethylaminopyridine (0.8 g). This solutionwas divided into three portions. To each portion was added a sulfonylchloride (2.2 mmol) and the mixtures were stirred overnight at 40° C.The reactions were worked up by adding to water (150 mL), extracting theproduct into ethyl acetate, washing with water, drying over MgSO₄ andevaporating. Each of the crude boc protected products was purified byflash chromatography (ethyl acetate:petrol 1:1). They were thendeprotected directly by dissolving in methanol (10 mL), adding asolution of HCl in ethyl acetate (1N, 50 mL) and stirring for 2 hours.The products were precipitated with ether (500 mL), collected byfiltration and dried under vacuum. The products obtained were:

Example 49

N-{4-(1,4-diazepan-1-yl)-2-[ethyl(methylsulfonyl)-amino]phenyl}-4-methylbenzenesulfonamidehydrochloride (Scheme 2, Method 4)

Was obtained from toluene sulfonyl chloride: Yield 0.36 g ¹H NMR (400MHz, DMSO-d₆) δ 0.79 (t, J=7.08 Hz, 3 H), 2.04 (m, 2 H), 2.37 (s, 3 H),3.07 (s, 3 H), 3.02-3.12 (br, 2 H), 3.12-3.20 (br, 2 H), 3.45 (t, J=5.85Hz, 2 H), 3.50 (q, J=7.08 Hz, 2 H), 3.67 (br, 2 H), 6.65-6.73 (m, 2 H),6.94 (d, J=9.03 Hz, 1 H), 7.38 (ab, J=8.06 Hz, 2 H), 7.70 (ab, J=8.06Hz, 2 H), 8.52 (s, 1 H), 9.2 (br s, 2 H) MS (ESI+) for C₂₁H₃₀N₄O₄S₂ m/z466.1722 M⁺ (Calc 466.1708).

Example 50

N-{4-(1,4-diazepan-1-yl)-2-[ethyl-(methylsulfonyl)-amino]phenyl}-3,4-dimethoxybenzenesulfonamidehydrochloride (Scheme 2, Method 4)

Was obtained from 3,4-dimethoxybenzenesulfonyl chloride: Yield 0.43 g ¹HNMR (400 MHz, DMSO-d₆) δ 0.81 (t, J=7.08 Hz, 3 H), 2.05 (m, 2 H), 3.08(s, 3 H), 3.03-3.11 (br, 2 H), 3.11-3.19 (br, 2 H), 3.45 (t, J=6.10 Hz,2 H), 3.52 (q, J=7.08 Hz, 2 H), 3.68 (br t, J=5.13 Hz, 2 H), 3.77 (s, 3H), 3.81 (s, 3 H), 6.66-6.74 (m, 2 H), 6.97 (d, J=8.79 Hz, 1 H), 7.09(d, J=8.55 Hz, 1 H), 7.33-7.4 (m, 2 H), 8.49 (s, 1 H), 9.3 (br s, 2 H)MS (ESI+) for C₂₂H₃₂N₄O₆S₂ m/z 512.1759 M⁺ (Calc 512.1763).

Example 51

N-{4-(1,4-diazepan-1-yl)-2-[ethyl(methyl-sulfonyl)amino]phenyl}-8-quinolinesulfonamidehydrochloride (Scheme 2, Method 4)

Was obtained from 8-quinoline sulfonyl chloride: Yield 0.46 g ¹H NMR(400 MHz, DMSO-d₆) δ 0.17 (t, J=7.08 Hz, 3 H), 2.06 (m, 2 H), 2.93 (s, 3H), 3.0-3.2 (m, 6 H), 3.47 (t, J=5.86Hz, 2 H), 3.70 (t, J=5.12Hz, 2 H),6.59 (m, 1 H), 6.77 (d m, J=9 Hz, 1 H), 7.31 (d, J=9 Hz, 1 H), 7.65-7.75(m, 2 H), 8.24 (d, J=7.32 Hz, 1 H), 8.29 (d, J=9.5 Hz, 1 H), 8.55 (dd,J=8.55, 1.71 Hz, 1 H), 9 (br, 1 H), 9.09 (dd, J=4.16, 1.71 Hz, 1 H), 9.3(br, 2 H); MS (ESI+) for C₂₃H₂₉N₅O₄S₂ m/z 503.1667 M⁺ (Calc 503.1661).

Intermediate 14

N-(5-fluoro-2-nitrophenyl)methanesulfonamide (Scheme 2, Method 4)

2,4-di-Nitrobenzene (5.5mL, 50 mmol), methanesulfonamide (4.75 g, 50mmol) and potassium carbonate (10 g) were stirred together in DMSO (100mL) at 80° C. overnight. Water (300 mL) was added followed byhydrochloric acid (1N, 300 mL). The solid product was collected byfiltration, washed with water and dried. Yield 9.57 g (82%) ¹H NMR (400MHz, CDCl₃) δ 3.2 (s, 3 H), 6.92 (m, 1 H), 7.64 (dd, J=10.5, 2.7 Hz, 1H), 8.34 (dd, J=9.5, 5.6 Hz, 1 H), 10.0 (brs, 1 H); MS (ESI+) forC₇H₇FN₂O₄S m/z 234 M⁺.

Intermediate 15

N-(5-Fluoro-2-nitrophenyl)-N-methylmethanesulfonamide (Scheme 2, Method4)

N-(5-fluoro-2-nitrophenyl)methanesulfonamide compound (5 g, 21 mmol),methyl iodide (3 mL) and potassium carbonate (10 g) were stirredtogether in DMSO (100 mL) at 80° C. overnight. The reaction was notcomplete and a further 1 mL of methyl iodide was added. After a further24 hours at 80° C., water (100 mL) was added. The solution was decantedfrom a small amount of sticky residue. The product crystallized out fromthe aqueous solution (48 hours) and was collected by filtration, washedwith water and dried. Yield 3.3 g (63%); ¹H NMR (400 MHz, CDCl₃) δ 3.04(s, 3 H), 3.30 (s, 3 H), 7.20 (m, 1 H), 7.31 (dd, J=8.54, 2.68 Hz, 1 H),8.0 (dd, J=9.3, 5.6 Hz, 1 H); MS (ESI+) for C₈H₉FN₂O₄S m/z 248 M⁺.

Intermediate 16

tert-Butyl-4-{3-[methyl(methylsulfonyl)amino]-4-nitrophenyl}-1,4-diazepane-1-carboxylate(Scheme 2, Method 4)

N-(5-Fluoro-2-nitrophenyl)-N-methylmethanesulfonamide (3.1 g, 12.5mmol), tert-butyl-1-homopiperazinecarboxylate (2.5 g) and potassiumcarbonate (2 g) were heated together in DMSO (50 mL) at 80° C.overnight. The solution was allowed to cool and poured into 500 mL ofwater. The solid product was collected by filtration, washed with waterand dried. Yield 4.6 g (86%); ¹H NMR (400 MHz, CDCl₃) δ 1.41 (s, 9 H),2.0 (br s, 2 H), 3.01 (s, 3 H), 3.28 (s, 3 H), 3.3-3.8 (br, 8 H), 6.64(d, J=8.1 Hz, 1 H), 6.74 (d, J=4.8 Hz, 1 H), 8.09 (d, J=8.1 Hz, 1 H); MS(ESI+) for C₁₈H₂₈N₄O₆S m/z 428.1709 (M⁺) (calc. 428.1730).

Preparation ofN-{4-(1,4-diazepan-1-yl)-2-[methyl(methylsulfonyl)amino]phenyl}-sulfonamides

tert-Butyl-4-{3-[methyl(methylsulfonyl)amino]-4-nitrophenyl}-1,4-diazepane-1-carboxylate(2.5 g, 5.7 mmol) was dissolved in THF (50 mL) and methanol (5 mL).Raney nickel (0.5 g) was added followed by hydrazine hydrate (0.5 mL).Nitrogen was evolved and the mixture stirred for 1 hour. The reactionmixture was absorbed onto a bed of silica gel and eluted withCH₂Cl₂:MeOH:NH₄OH (9:1:0.01 200 mL). The solvent was removed byevaporation, toluene (200 mL) was added and evaporated to remove anywater and hydrazine. The crude amine (2.36 g) was dissolved inacetonitrile (50 mL) with dimethylaminopyridine (0.8 g). This solutionwas divided into six portions. To three of these portions was added asulfonyl chloride (1.1 mmol) and the mixtures were stirred overnight at40° C. The reactions were worked up by adding ethyl acetate (50 mL),washing with brine and water, drying over MgSO₄ and evaporating. Each ofthe crude boc protected products was purified by flash chromatography(ethyl acetate:petrol 2:1). They were then deprotected directly bydissolving in methanol (10 mL), adding a solution of HCl in ethylacetate (1N, 50 mL) and stirring for 2 hours. The products wereprecipitated with ether (500 mL), collected by filtration and driedunder vacuum.

Example 52

N-{4-(1,4-diazepan-1-yl)-2-[methyl(methylsulfonyl)-amino]phenyl}-4-methylbenzenesulfonamidehydrochloride (Scheme 2, Method 4)

Was obtained from toluene sulfonyl chloride: Yield 0.18 g ¹H NMR (400MHz, DMSO-d₆) δ 2.04 (br m, 2 H), 2.36 (s, 3 H), 2.72 (s, 3 H), 3.05 (s,3 H), 3.1-3.4 (m, 4 H), 3.46 (t, J=6.34 Hz, 2 H), 3.70 (t, J=4.88 Hz, 2H), 6.69 (d, J=2.7 Hz, 1 H), 6.72 (s, 1 H), 6.95 (d, J=8.78 Hz, 1 H),7.36 (ab, J=8.54 Hz, 2 H), 7.57 (ab, J=8.54 Hz, 2 H), 8.39 (s, 1 H),9.24 (brs, 2 H); MS (ESI+) for C₂₀H₂₈N₄O₄S₂ m/z 452.1545 M⁺ (Calc.452.1552).

Example 53

N-{4-(1,4-diazepan-1-yl)-2-[methyl-(methyl-sulfonyl)amino]phenyl}-naphthalene-2-sulfonamidehydrochloride (Scheme 2, Method 4)

Was obtained from 2-naphthalenesulfonyl chloride: Yield 0.09 g ¹H NMR(400 MHz, DMSO-d₆) δ 2.0 (br m, 2 H), 2.66 (s, 3 H), 3.05 (s, 3 H),3.0-3.4 (m, 4 H), 3.43 (t, J=7.08 Hz, 2 H), 3.66 (br t, J=5.1 Hz, 2 H),6.65 (dd, J=9.0, 2.9 Hz, 1 H), 6.68 (s, 1 H), 6.90 (d, J=9.0 Hz, 1 H),7.65 (q, J=8.0 Hz, 1 H), 7.68 (q, J=8.3 Hz, 1 H), 7.8 (d, J=6.8 Hz, 1H), 8.04 (d, J=7.8 Hz, 1 H), 8.12 (t, J=8.8 Hz,2 H),8.32 (s, 1 H), 8.68(s, 1 H), 9.2 (br, 2 H); MS (ESI+) for C₂₃H₂₈N₄O₄S₂ m/z 488.1529 M⁺(Calc. 488.1552).

Example 54

N-{4-(1,4-diazepan-1-yl)-2-[methyl(methylsulfonyl)amino]phenyl}-5-(2-pyridinyl)-2-thiophenesulfonamidehydrochloride (Scheme 2, Method 4)

Was obtained from 5-(2-pyridinyl)thiophene-2-sulfonyl chloride: Yield0.12 g ¹H NMR (400 MHz, DMSO-d₆) δ 2.05 (br m, 2 H), 2.90 (s, 3 H), 3.07(s, 3 H), 3.1-3.4 (m, 4 H), 3.48 (t, J=6.1 Hz, 2 H), 3.71 (m, 2 H), 6.75(dd, J=9.0, 2.7 Hz, 1 H), 6.78 (s, 1 H), 7.03 (d, J=8.8 Hz, 1 H), 7.39(dd, J=7.6, 4.2 Hz, 1 H), 7.50 (d, J=4.2 Hz, 1 H), 7.84 (d, J=3.9 Hz, 1H), 7.91 (td, J=7.6, 1.7 Hz, 1 H), 8.03 (d, J=7.8 Hz, 1 H), 8.56 (d,J=4.9 Hz 1 H), 8.81 (s, 1 H), 9.3 (br, 2 H); MS (ESI+) for C₂₂H₂₇N₅O₄S₃m/z 521.1200 M⁺ (Calc. 521.1225).

Scheme 3

To a solution of N-{2-amino-5-(4-t-butyloxycarbonyl-1,4-diazepan-1-yl)-phenyl}benzenesulfonamide (92.5 mg, 0.207 mmol) and pyridine (131 μL,1.6 mmol) in DCM (7 mL), the sulfonylchloride (0.27 mmol) was added.After 2 h at r.t. the solvent was removed. Purification bycolumnchromatography (CH₂Cl₂/MeOH/Heptane, 4:1:15) followed byBoc-deprotection which was achieved by dissolving the residue in smallamount of MeOH and adding HCl/ether. The mixture was left at r.t. for0.5 h after which the solvent was removed. Recrystallization(MeOF/ether) afforded the final product.

Example 55

N-{4-(1,4-diazepan-1-yl)-2-[(phenylsulfonyl)amino]phenyl}-1-naphthalenesulfonamidehydrochloride (Scheme 3)

The compound was synthesized from ofN-{2-amino-5-(4-t-butyloxycarbonyl-1,4-diazepan-1-yl)-phenyl}benzenesulfonamide and 1-naphthalenesulfonylchloride (61 mg, 0.27mmol) to give 56 mg as purple solid. M+1 537.2 Calcd 537.15; ¹HNMR δ8.67-8.64 (m, 1H), 8.10 (d, 1H), 8.02-7.98 (m, 1H), 7.89 (dd, 1H),7.77-7.38 (m, 8H), 6.46 (d, 1H), 6.26 (d, 1H), 6.14 (dd, 1H), 3.54 (appt, 2H), 3.36-3.31 (m, 2H), 3.17 (app t, 2H), 2.05-1.96 (m, 2H).

Example 56

N-{4-(1,4-diazepan-1-yl)-2-[(phenylsulfonyl)amino]phenyl}-5-(dimethylamino)-1-naphthalenesulfonamidehydrochloride (Scheme 3)

The compound was synthesized from ofN-{2-amino-5-(4-t-butyloxycarbonyl-1,4-diazepan-1-yl)-phenyl}benzenesulfonamideand dansylchloride (73 mg, 0.27 mmol) to give 51 mg AS purple solid. M+1580.3 Calcd 580.20; ¹HNMR δ 8.86 (d, 1H), 8.62 (d, 1H), 8.08-7.46 (m,9H), 6.64 (d, 1H), 6.32 (dd, 1H), 6.14 (d, 1H), 3.53 (app t, 2H), 3.45(s, 6H), 3.16-3.06 (m, 4H), 2.03-1.95 (m, 2H).

Example 57

N-{4-(1,4-diazepan-1-yl)-2-[(phenylsulfonyl)amino]phenyl}-8-quinolinesulfonamidehydrochloride (Scheme 3)

The compound was synthesized from ofN-{2-amino-5-(4-t-butyloxycarbonyl-1,4-diazepan-1-yl)-phenyl}benzenesulfonamide and 8-quinolinesulfonylchloride (61 mg, 0.27mmol) to give 34 mg of a purple solid. M+1 538.2 Calcd 538.15.

Example 58

N-{4-(1,4-diazepan-1-yl)-2-[(phenylsulfonyl)amino]phenyl}-2,4,6-trimethylbenzenesulfonamidehydrochloride (Scheme 3)

The compound was synthesized from ofN-{2-amino-5-(4-t-butyloxycarbonyl-1,4-diazepan-1-yl)-phenyl}benzenesulfonamide and 2-mesitylenesulfonylchloride (59 mg, 0.27mmol) to give 56 mg as purple solid. M+1 529.3 Calcd 529.70; ¹HNMR δ7.80-7.47 (m, 5H), 6.93 (s br, 2H), 6.64 (d, 1H), 6.46-6.39 (m, 2H),3.60 (app t, 2H), 3.39 (app t, 2H), 3.21 (app t, 2H), 3.12 (app t, 2H),2.36 (s, 6H), 2.26 (s, 3H), 2.08-2.00 (m, 2H).

Example 59

N-{4-(1,4-diazepan-1-yl)-2-[(phenylsulfonyl)amino]phenyl}-4-methylbenzenesulfonamidehydrochloride (Scheme 3)

The compound was synthesized from ofN-{2-amino-5-(4-t-butyloxycarbonyl-1,4-diazepan-1-yl)-phenyl}benzenesulfonamide and p-toluenesulfonylchloride (51 mg, 0.27mmol) to give 22 mg as purple solid. M+1 501.3 Calcd 501.15; ¹HNMR δ7.77-7.26 (m, 9H), 6.54 (d, 1H), 6.50 (d, 1H), 6.40 (dd, 1H), 3.63 (appt, 2H), 3.42 (app t, 2H), 3.25 (app t, 2H), 3.16 (app t, 2H), 2.38 (s,3H), 2.11-2.03 (m, 2H).

Example 60

N-[5-(1,4-diazepan-1-yl)-2-({[(E)-2-phenylethenyl]sulfonyl}amino)phenyl]benzenesulfonamidehydrochloride (Scheme 3)

The compound was synthesized from ofN-{2-amino-5-(4-t-butyloxycarbonyl-1,4-diazepan-1-yl)-phenyl}benzenesulfonamide and beta-styrenesulfonylchloride (55 mg, 0.27mmol) to give before Boc-deprotection 12 mg as purple solid. M+1 513.6Calcd 512.15; ¹HNMR δ 7.78-7.38 (m, 10H), 7.20 (d, 1H), J=15.4 Hz), 7.10(d, 1H), 6.98 (d, 1H), J=15.4 Hz), 6.56 (dd, 1H), 6.44 (d, 1H), 3.62(app t, 2H), 3.41 (app t, 2H), 3.23 (app t, 2H), 3.15 (app t, 2H),2.09-2.01 (m, 2H).

Example 61

N-{4-(1,4-diazepan-1-yl)-2-[(phenylsulfonyl)amino]phenyl}-2,5-dimethoxybenzenesulfonamidehydrochloride (Scheme 3)

The compound was synthesized from ofN-{2-amino-5-(4-t-butyloxycarbonyl-1,4-diazepan-1-yl)-phenyl}benzenesulfonamideand 2,5-dimethoxybenzenesulfonylchloride (64 mg, 0.27 mmol) to give 14mg as purple solid. M+1 547.3 Calcd 547.16; ¹HNMR δ 7.71-7.00 (m, 9H),6.48 (dd, 1H), 6.16 (d, 1H), 4.04 (s, 3H), 3.68 (s, 3H), 3.56 (app t,2H), 3.33 (app t, 2H), 3.17 (app t, 2H), 3.11 (app t, 2H), 2.03-1.95 (m,2H).

Example 62

N-{4-(1,4-diazepan-1-yl)-2-[(phenylsulfonyl)amino]phenyl}-2-methylbenzenesulfonamidehydrochloride (Scheme 3)

The compound was synthesized from ofN-{2-amino-5-(4-t-butyloxycarbonyl-1,4-diazepan-1-yl)-phenyl}benzenesulfonamide and o-toluenesulfonylchloride (51 mg, 0.269mmol) to give 18 mg as purple solid. M+1 501.3 Calcd 501.15; ¹HNMR δ7.78-7.17 (m, 9H), 6.68-6.35 (m, 3H), 3.63-3.10 (m, 8H), 2.59 (s, 3H),2.09-2.01 (m, 2H).

Example 63

4-Butoxy-N-{4-(1,4-diazepan-1-yl)-2-[(phenylsulfonyl)amino]phenyl}-benzenesulfonamidehydrochloride (Scheme 3)

The compound was synthesized from ofN-{2-amino-5-(4-t-butyloxycarbonyl-1,4-diazepan-1-yl)-phenyl}benzenesulfonamide and 4-n-butoxybenzenesulfonylchloride (67 mg,0.269 mmol) to give 27 mg as purple solid. M+1 559.4 Calcd 559.20; ¹HNMRδ 7.77-7.47 (m, 7H), 6.96-6.93 (m, 2H), 6.55 (d, 1H), 6.52 (d, 1H), 6.41(d, 1H), 4.01 (t, 2H), 3.63 (app t, 2H), 3.43 (app t, 2H), 3.25 (app t,2H), 3.17 (app t, 2H), 2.11-2.03 (m, 2H), 1.80-1.71 (m, 2H), 1.53-1.45(m, 2H), 0.98 (t, 3H).

Example 64

N-{4-(1,4-diazepan-1-yl)-2-[(phenylsulfonyl)amino]phenyl}-3,5-dimethyl-4-isoxazolesulfonamidehydrochloride (Scheme 3)

The compound was synthesized from ofN-{2-amino-5-(4-t-butyloxycarbonyl-1,4-diazepan-1-yl)-phenyl}benzenesulfonamide and 3,5-dimethylisoxazolesulfonylchloride (53mg, 0.269 mmol) to give 32 mg as purple solid. M+1 506.3 Calcd 506.15;¹HNMR δ 7.75-7.48 (m, 5H), 6.92 (d, 1H), 6.59 (dd, 1H), 6.28 (d, 1H),3.62 (app t, 2H), 3.41 (app t, 2H), 3.21 (app t, 2H), 3.12 (app t, 2H),2.23 (s, 3H), 2.13 (s, 3H), 2.09-2.01 (m, 2H).

Example 65

N-{4-(1,4-diazepan-1-yl)-2-[(phenylsulfonyl)amino]phenyl}-5-fluoro-2-methylbenzenesulfonamidehydrochloride (Scheme 3)

The compound was synthesized from ofN-{2-amino-5-(4-t-butyloxycarbonyl-1,4-diazepan-1-yl)-phenyl}benzenesulfonamide and 5-fluoro-2-methylbenzenesulfonylchloride(56 mg, 0.269 mmole) to give 7 mg as purple solid. M+1 519.3 Calcd519.15; ¹HNMR δ 7.78-7.18 (m, 8H), 6.72 (d, 1H), 6.45 (dd, 1H), 6.34 (d,1H), 3.59 (app t, 2H), 3.38 (app t, 2H), 3.21 (app t, 2H), 3.13 (app t,2H), 2.57 (s, 3H), 2.06-1.98 (m, 2H).

Example 66

N-{4-(1,4-diazepan-1-yl)-2-[(phenylsulfonyl)amino]phenyl}-4-(methylsulfonyl)benzenesulfonamidehydrochloride (Scheme 3)

The compound was synthesized from ofN-{2-amino-5-(4-t-butyloxycarbonyl-1,4-diazepan-1-yl)-phenyl}benzenesulfonamideand 4-methylsulfonylbenzenesulfonylchloride (69 mg, 0.269 mmole) to give38 mg as purple solid. M+1 565.3 Calcd 565.12; ¹HNMR δ 8.08-7.48 (m,9H), 6.76 (d, 1H), 6.48 (dd, 1H), 6.32 (d, 1H), 3.61 (app t, 2H), 3.38(app t, 2H), 3.21 (app t, 2H), 3.17 (app t, 2H), 3.14 (app t, 2H),2.08-2.00 (m, 2H).

Example 67

N-{4-(1,4-diazepan-1-yl)-2-[(methylsulfonyl)amino]phenyl}-N-methylbenzenesulfonamide(Scheme 3)

N-methyl-{2-amino-5-(4-t-butyloxycarbonyl-1,4-diazepan-1-yl)-phenyl}-benezenesulfonamide (0.196 g, 0.426 mmol) was dissolved inpyridine (1.67 ml) followed by the addition of methyl sulphonylchloride(57 mg, 0.50 mmol) The ractiom was stirred at rt for 3 h. The mixturewas concentrated and treated with trifluoroacetic acid (50%) in DCM for30 min then concentrated and left for our HPLC Separation specialists.Further purification by column cheomatography DCM/MeOH (9:1) afforded 32mg, 0.058 mmol in 13% yield of the title compound. ¹H NMR (CD₃OD) δ 2,17(m, 2 H), 3,05 (s, 3 H), 3,14 (s, 3 H), 3,27 (m, 2 H), 3,38 (m, 2 H),3,57 (m, 2 H), 3,77 (m, 2 H), 6,28 (d, 1 H), 6,41 (dd, 1 H), 7,06 (d, 1H), 7,65 (m, 5 H); ¹³C NMR (CD₃OD) δ 25,0, 38,7, 39,0, 45,1, 45,5, 45,8,47,0, 100, 103,9, 108,1, 121,4, 125, 126, 128, 133,4, 136, 137,5, 148,5;M/Z Calc for (C₁₉H₂₆N₄O₄S₂) 438.14 found M⁺+1=439.2

Example 68

N-{5-(1,4-diazepan-1-yl)-2-[methyl(phenylsulfonyl)amino]phenyl}-4-methylbenezenesulfonamide(Scheme 3)

N-methyl-{2-amino-5-(4-t-butyloxycarbonyl-1,4-diazepan-1-yl)-phenyl}-benzenesulfonamide (0.196 g, 0.426 mmol) was dissolved inpyridine (1.67 ml) followed by the addition ofp-methylphenyl-sulphonylchlride (88 mg, 0.50 mmol) the reaction wasstirred at rt for 3 h. The mixture was concentrated and treated withtrifluoroacetic acid (50%) in DCM for 30 min then concentrated and leftfor our HPLC Separation specialists. Further purificaction by flashcolumn chromatography DCM/MeOH (9:1) afforded 0.110 g, 0.175 mmol in 40%yield of title compound. ¹H NMR (CD₃OD) δ 2,17 (m, 2 H),2,52, (s,3H),3,0-3,4 (m, 7 H), 3,52 (m, 2 H), 3,74 (m, 2 H), 6,15 (d, 1 H), 6,41 (d,1 H), 6,92 (s, 1 H), 7,5-7.80 (m, 6 H); M/Z Calc for (C₂₅H₃₀N₄O₄S₂)514.1708 found M⁺ 514.1708.

General Method for the Preparation of Monosulfonamides

Example 69

N-[2-Amino-4-(1-piperazinyl)phenyl]-3-fluorobenzenesulfonamide (Scheme4)

tert-Butyl 4-(3-amino-4-nitrophenyl)-1-piperazinecarboxylate (1.5 g, 3.5mmol) was dissolved in methanol:THF (4:1). Raney-Ni (900 mg) was addedfollowed by addition of hydrazine monohydrate (900 mg). The reaction wasstirred at r. t. under N₂ atmosphere overnight. Starting material waspresent. Raney-Ni (400 mg) was added and the reaction was stirredovernight. The reaction was filtered through celite pad followed bywashings with ethanol. The volatiles were evaporated to afford 93% of2-amino-5-(4-t-buthylcaboxyl-1-piperazinyl)aniline.

2-amino-5-(4-t-buthylcaboxyl-1-piperazinyl) aniline (150 mg, 0.382 mmol)was dissolved in CH₂Cl₂ (2 mL). 3-fluorophenylsulfonylchloride (74 mg,0.382 mmol), pyridine (215 μL, 2.67 mmol) were added and the reactionwas stirred at room temperature for 2 hr. The reaction was quenched withNaHCO₃ (saturated aqueous solution), extracted with CH₂Cl₂. The organicphase was dried (MgSO₄), filtered and concentrated to give an oilresidue that was purified by flash column chromatography (SiO₂,CH₃Cl:MeOH:NH₃ 9:1:0.4%) to afford ofN-[2-amino-4-(4-tert-butylcarboxyl-1-piperazinyl)-3fluorobenzenesulfonamide (80%).

N-[2-amino-4-(4-tert-butylcarboxyl-1-piperazinyl)-3-fluorobenzenesulfonamide(110 mg) were dissolved in methanol (0.5 mL) followed by the addition ofdiethylether (2 mL). Ether/HCl gas was added till pH=1. The reaction wasstirred at room temperature for 5 h to afford the title product as awhite solid ¹H NMR (methanol-d3) δ 3.25-3.50 (m, 8H); 6.5 (d, 1H); 6.75(dd, 1H), 7.0 (bs, 1H); 7.3-7.6 (m, 4H); MS (posEI-DIP) m/z=351.2 (M+H).

Example 70

N-[2-(ethylamino)-4-(4-methyl-1-piperazinyl)phenyl]-3-fluorobenzenesulfonamidehydrochloride (Scheme 4)

To a solution of N-2-ethyl-4-(4-methyl-1-piperazinyl)-1,2-benzenediamine(0.200 g, 0.853 mmol) and pyridine (0.48 mL, 5.97 mmol) in DCM (8 mL)was added a solution of 3-fluorobenzenesulfonyl chloride (249 mg, 1.28mmol) in DCM (2 mL). The mixture was stirred at room temperature for 16hours. DCM (10 mL) was added and the mixture was washed with saturatedaqueous NaHCO₃. The organic layer was dried over Na₂SO₄, filtered andconcentrated. Column chromatography on Al₂O₃ using EtOAc/5% MeOH aseluent gave two products. First fraction contains 110 mg ofN-[2-{ethyl[(3-fluorophenyl)sulfonyl]amino}-4-(4-methyl-1-piperazinyl)phenyl]-3-fluorobenzenesulfonamidehydrochloride. Second fraction contains 100 mg ofN-[2-(ethylamino)-4-(4-methyl-1-piperazinyl)phenyl]-3-fluorobenzenesulfonamidehydrochloride. Both products were converted to the HCl-salts.N-[2-(ethylamino)-4-(4-methyl-1-piperazinyl)phenyl]-3-fluorobenzenesulfonamidehydrochloride: ¹H NMR (DMSO-d6) δ 11.24 (br s, 1H), 9.76 (br s, 1H),7.66-7.59 (m, 1H), 7.56-7.50 (m, 3 H), 6.62 (app d, J=8.8 Hz, 1H),6.55-6.35 (m, 2H), 3.80-3.70 (m, 2 H), 3.46-3.40 (m, 2H), 3.15-2.96 (m,6H), 2.76 (app d, J=4.4 Hz, 3H), 1.08 (tr, J=7.2 Hz,3H); 13C NMR (CD₃OD)δ 61.03 (d, J_(CF)=248 Hz), 149.32, 142.13 (d, J_(CF)=6.4 Hz), 140.72,131.43 (d, J_(CF)=7.4 Hz), 128.56, 123.22, 119.93 (d, J_(CF)=20 Hz),115.91, 113.86 (d, J_(CF)=24 Hz), 107.78, 103.12, 51.83, 45.04, 41.80,40.62, 12.88; AccMs (posES-FIA) found: 392.1672, calc: 392.1782; Ms(posES-FIA) m/z 393 (M+H).

Example71

4-Chloro-N-[5-(4-methyl-1,4-diazepan-1-yl)-2-nitrophenyl]benzenesulfonamide(Scheme 4)

4-chlorobenzene sulfonamide (3.5 g, 18.3 mmol) was added slowly to asuspension of sodium hydride (1.6 g, 55% suspension in mineral oil, 36.6mmol) in anhydrous DMF (50 mL) under an atmosphere of nitrogen. Themixture was warmed to 40° C. for 1 hour and 2,4-difluoronitrobenzene (2mL) was added dropwise. This mixture was stirred at 60° C. overnight.The cooled reaction mixture was poured into hydrochloric acid (1 N, 250mL) and extracted with ethyl acetate (2×50 mL). The organic extractswere washed with water, dried over MgSO₄ and evaporated to give a yellowsolid. The product was re-crystallized from ethanol. Yield 2.4 g (40%).¹H NMR (400 MHz, CDCl₃) δ 6.85 (m, 1 H), 7.48 (AB, J=8.3 Hz, 2 H), 7.56(dd, J=10.01, 2.68 Hz, 1 H), 7.84 (AB, J=8.3 Hz, 2 H), 8.21 (dd, J=5.61Hz, 1 H), 10 (bs, 1 H). Calculated N 8.47%, C 43.58%, S 9.70%, H 2.44%;Found N 8.54%, C43.89%, S10.10%, H 2.76%.4-Chloro-N-[5-fluoro-2-nitrophenyl]benzenesulfonamide (1 g, 3 mmol) andN-methylhomopiperazine (0.4 mL) were heated together at 130° C. for 3hours. The product was allowed to cool, dissolved in CH₂Cl₂ (50 mL) andwashed with aqueous sodium bicarbonate. The organic phase was dried overMgSO₄ and evaporated to give 1.05 g of a yellow solid which wasre-crystallized from toluene. Yield 0.65 g (51%). ¹H NMR (400 MHz,CDCl₃) δ 1.98 (q, J=5.62 Hz, 1 H), 2.37 (s, 3 H), 2.52 (t, J=5.62 Hz, 2H), 2.67 (t, J=5.12 Hz, 2 H), 3.55 (t, J=6.35 Hz, 2 H), 3.60 (t, J=5.12Hz, 2 H), 6.34 (dd, J=9.77, 2.68 Hz, 1 H), 6.86 (d, J=2.68 Hz, 1 H),7.43 (ab, J=8.79 Hz, 2H), 7.79 (ab, J=8.79 Hz, 2H), 8.01 (d, J=9.77 Hz,1 H), 11.6 (brs, 1 H). Calculated N 13.19%, C 50.88%, H 4.98%; Found N13.27%, C 50.99%, H 4.83%.

Example 72

N-[2-amino-5-(1,4-diazepan-1-yl)phenyl]benzenesulfonamide (Scheme 4)

N-{5-(4-t-butyloxycarbonyl-1,4-diazepan-1-yl)-2-nitro-phenyl}benzenesulfonamide(1.85 g, 3.88 mmol) was dissolved in EtOH/THF (1:4). Hydrazine (0.970rnL, 19.4 mmol) and Raney-Ni (0.180 g) was added. After 1 h at roomtemperature, the reaction was filtered through wet celite and thesolvent was removed to afford 1.71 g of colorless oil. Boc-deprotectionwas achieved by dissolvingN-{5-(4-t-butyloxycarbonyl-1,4-diazepan-1-yl)-2-amino-phenyl}benzenesulfonamide(0.039 g) in small amount of MeOH and adding HCl/ether. The mixture wasleft at room temperature for 0.5 h after which the solvent was removed.Re-crystallization from MeOH/ether gave PHA-509592A (23 mg) as a whitesolid. M+1 347.4 Calcd 347.15; ¹H-NMR δ 7.73-7.54 (m, 5H), 7.30 (d, 1H),6.84 (dd, 1H), 5.78 (d, 1H), 3.55 (app t, 2H), 3.32-3.26 (m, 2H),3.13-3.08 (m, 4H), 2.03-1.92 (m, 2H).

Example 73

N-[2-amino-5-(4-methyl-1,4-diazepan-1-yl)phenyl]benzenesulfonamidehydrochloride (Scheme 4)

The above sulfonamide (0.6 g, 1.8 mmol) in methanol (50 mL) withPalladium (10% on C, 0.3 g) was hydrogenated at atmospheric pressure forone hour during which time 140 mL of hydrogen was consumed. The solutionwas filtered and evaporated to give colorless oil. The oil was dissolvedin toluene (20 mL) and treated with a solution of hydrogen chloride inethyl acetate. The product was triturated with cyclohexane, collected byfiltration and dried. Yield 0.44 g (73%). A portion was recrystallizedfrom toluene:ethanol 1:1. ¹H NMR (400 MHz, CDCl₃) δ 1.95 (br, 1 H), 2.17(br, 1 H), 2.72 (s, 3 H), 2.80-3.65 (br m, 8 H), 5.92 (br, 1 H), 6.66(dd, J=2.69, 9.03 Hz, 1 H), 7.20 (d, J=9.03 Hz, 1 H), 7.63 (t, J=7.81Hz, 2 H), 7.71 (t, J=7.32 Hz, 1 H), 7.81 (d, J=7.32 Hz, 2 H), 9.8 (br, 3H), 11 (br, s 1 H). MS (ESI+) for C₁₈H₂₄N₄O₂S m/z 360.1634 (M+)⁺(Calculated 360.1620)

Example 74

N-[4-Nitro-3-(1-piperazinyl)phenyl]benzenesulfonamide hydrochloride(Scheme 4)

A mixture of difluoronitrobenzene (1.31 g, 8.21 mmol), Boc-piperazine(1.84 g, 9.8 mmol) and K₂CO₃ in DMF was stirred at room temperatureovernight. The mixture was filtered and the DMF was removed. The residuewas dissolved in CH₂Cl₂ and extracted with HCl (1M) three times. Theorganic layers were dried (MgSO₄), filtered and the solvent was removed.Purification by column chromatography (SiO₂, CH₂Cl₂/heptane, 1:4) gave1.14 g of yellow solid. ¹H-NMR δ 7.90 (dd, 1H), 6.77-6.69 (m, 2H),3.60-3.57 (m, 4H), 3.03-3.00 (m, 4H), 1.46 (s, 9H); MS (posEI-DIP)m/z=Found: 348.2 (M⁺+Na⁺). NaH (17.2 mg, 0.43 mmol) was added to asolution of 4-(2-nitro-5-fluorophenyl)-1-(t-butyloxycarbonyl)piperazine(0.079 g, 0.215 mmol) and benzensulfonamide (0.044 g, 0.280 mmol) inDMF. The mixture was heated at 80° C. over night and filtered.Purification by column chromatography (SiO₂, CH₂Cl₂/heptane, 1:4) gave0.075 g ofN-[2-nitro-4-(t-butyloxycarbonylpiperazinyl)]phenyl]benzenesulfonamideof which 0.025 mg was Boc-deprotected by dissolving the compound in MeOHand adding HCl/ether. The mixture was stirred for 0.5 h after which thesolvent was removed. Re-crystallization MeOH/ether gave 24.6 mg of ayellow solid. ¹H-NMR δ 7.88 (app d, 3H), 7.63-7.52 (m, 3H), 7.07 (d,1H), 6.89 (dd, 1H), 3.38-3.34 (m, 4H), 3.25-3.21 (m, 4H); MS (posEI-DIP)m/z=Found: 363.3 (M⁺+H⁺).

Example 75

N-[4-amino-3-(1-piperazinyl)phenyl]benzenesulfonamide hydrochloride(Scheme 4)

To a solution ofN-[2-nitro4-(t-butyloxycarbonylpiperazinyl)]phenyl]benzensulfonamide (50mg, 0.108 mmol) in THF/EtOH 4:1 was added Raney-Ni (5 mg) and hydrazinehydrate (27 μL, 0.54 mmol). The mixture was stirred at room temperaturefor 6 h followed by filtration of the reaction mixture through wetCelite. Removal of the solvent and purification by column chromatography(SiO₂, CH₂Cl₂/heptane/MeOH, 4:5:1) gaveN-[2-amino-4-(t-butyloxycarbonyl-piperazinyl)]phenyl]-benzenesulfonamide.Boc-deprotection was achieved by dissolving the compound in MeOH andadding HCl/ether. The mixture was stirred for 0.5 h after which thesolvent was removed. Re-crystallization (MeOH/ether) gave a white solidthat had to be purified by preparative HPLC to obtain 10 mg of the finalproduct. ¹H-NMR 8 7.66-7.45 (m, 5H), 6.78 (d, 1H), 6.62 (d, 1H), 6.50(dd, 1H), 3.39-3.35 (m, 4H), 3.02-2.99 (m, 4H); MS (posEI-DIP)m/z=Found: 333.0 (M⁺+H⁺).

4-Chloro-3-nitrobenzenesulfonyl chloride, taken from a prepared stocksolution, (1.78 mmol, 1.0 eq) in CH₂Cl₂ (2 mL) was added to a solutionof the appropriate R^(n)-substituted anilines (R¹-NH₂ or R¹-NH-R³) (1.62mmol, 1.0 equiv.) in the presence of pyridine (11.34 mmol, 7.0 equiv.).

The reactions were stirred overnight at room temperature. Each mixturewas washed with 1N HCl followed by NaHCO₃ (sat. aqueous). Each organicphase was separated, dried (Na₂SO₄), and filtered. CH₂Cl₂ (2 mL) wereadded to each reaction mixture followed by the addition of K₂CO₃ (3.24mmol, 2.0 equiv.) and homopiperazine or other amines of choice (i.e. R⁵)(2.11 mmol, 1.3 equiv.). Each reaction mixture was stirred at roomtemperature for 2 days. The volatiles were eliminated using a speed vac.Each reaction mixture was dissolved in a 4:1 EtOH:THF (25 mL) followedby addition of Raney-Ni (0.5 mL suspension in EtOH) and hydrazinemonohydrate (8.10 mmol, 5.0 equiv.). Each mixture was stirred at roomtemperature for 2 days and then filtered (Celite pad pretreated withwater). The filtrates were concentrated to give the crude products(LC-MS). An aliquot of each reaction mixture was purified by reversedphase preparative HPLC to give analytical samples which were convertedto their HCl-salts and sent for pharmacological testing.

Example 76

3-Amino-4-(1,4-diazepan-1-yl)-N-(4-methoxyphenyl)benzenesulfonamidehydrochloride (Scheme 5, Method 5)

The compound was prepared from p-anisidine; (crude yield 0.238 g, yieldanalytical pure sample 0.137 g); ¹H NMR (CDCl₃) δ 7.43-7.39 (m, 2H),7.37-7.33 (m, 1H), 7.00-6.96 (m, 2H), 6.78-6.74 (m, 2H), 3.71 (s, 3H),3.47-3.38 (m, 6H), 3.17-3.13 (m, 2H), 2.19-2.12 (m, 2H); MS (posESI)m/z=377 (M+H⁺).

Example 77

3-Amino-4-(1,4-diazepan-1-yl)-N-(3-methoxyphenyl)benzenesulfonamidehydrochloride (Scheme 5, Method 5)

The compound was prepared from m-anisidine; (crude yield 0.546 g, yieldanalytical pure sample 0.020 g); ¹H NMR (CDCl₃) 6 7.71-7.67 (m, 2H),7.51-7.47 (m, 1H), 7.12-7.07 (m, 1H), 6.72-6.69 (m, 1H), 6.68-6.65 (m,1H), 6.63-6.59 (m, 1H), 3.71 (s, 3H), 3.48-3.40 (m, 6H), 3.18-3.14 (m,2H), 2.21-2.15 (m, 2H); MS (posES-FIA) m/z=377 (M+H⁺).

Example 78

3-Amino-4-(1,4-diazepan-1-yl)-N-(2-methoxyphenyl)benzenesulfonamidehydrochloride (Scheme 5, Method 5)

The compound was prepared from o-anisidine; (crude yield 0.469 g, yieldanalytical pure sample 0.010 g); ¹H NMR (CDCl₃) 8 7.51-7.47 (m, 2H),7.42-7.35 (m, 2H), 7.11-7.06 (m, 1H), 6.89-6.82 (m, 2H), 3.57 (s, 3H),3.47-3.38 (m, 6H), 3.17-3.12 (m, 2H), 2.20-2.13 (m, 2H); MS (posES-FIA)m/z=377 (M+H⁺).

Example 79

3-Amino-4-(1,4-diazepan-1-yl)-N-(3-fluorophenyl)benzenesulfonamidehydrochloride (Scheme 5, Method 5)

The compound was prepared from 3-fluoroaniline; (crude yield 0.580 g,yield analytical pure sample 0.043 g); ¹H NMR (CD₃OD) δ 7.58-7.49 (m,2H), 7.41-7.35 (m, 1H), 7.23-7.17 (m, 1H), 6.93-6.87 (m, 2H), 6.79-6.73(m, 1H), 3.46-3.37 (m, 6H), 3.17-3.13 (m, 2H), 2.20-2.12 (m, 2H); MS(posES-FIA) m/z=365 (M+H⁺).

Example 80

3-Amino-4-(1,4-diazepan-1-yl)-N-methyl-N-phenylbenzenesulfonamidehydrochloride (Scheme 5, Method 5)

The compound was prepared from N-methylaniline; (crude yield 0.590 g,yield analytical pure sample 0.010 g); ¹H NMR (CD₃OD) δ 7.41-7.36 (m,1H), 7.35-7.22 (m, 5H), 7.15-7.11 (m, 2H), 3.50-3.44 (m, 6H), 3.23-3.17(m, 5H), 2.33-2.16 (m, 2H); MS (posEI) m/z=360 (M+H⁺).

Example 81

3-Amino-4-(1,4-diazepan-1-yl)-N-(4-isopropylphenyl)benzenesulfonamidehydrochloride (Scheme 5, Method 5)

The compound was prepared from 4-isopropylaniline; (crude yield 0.600 g,yield analytical pure sample 0.015 g); ¹H NMR (CD₃OD) δ 7.48-7.41 (m,2H), 7.35-7.31 (m, 1H), 7.10-7.05 (m, 2H), 7.03-6.98 (m, 2H), 3.47-3.35(m, 6H), 3.17-3.12 (m, 2H), 2.80 (sept, J=6.8 Hz, 1H), 2.20-2.10 (m,2H), 1.17 (d, J=6.8 Hz, 6H); MS (posEI) m/z=388 (M+H⁺).

Example 82

3-Amino-4-(1,4-diazepan-1-yl)-N-(4-methylphenyl)benzenesulfonamidehydrochloride (Scheme 5, Method 5)

The compound was prepared from p-toluidine; (crude yield 0.590 g, yieldanalytical pure sample 0.020 g); ¹H NMR (CD₃OD) δ 7.35-7.33 (m, 1H),7.31-7.27 (m, 1H), 7.25-7.22 (m, 1H), 7.03-6.94 (m, 4H), 3.47-3.30 (m,partly obscured by solvent signal, 6H), 3.16-3.11 (m, 2H), 2.23 (s, 3H),2.17-2.10 (m, 2H); MS (posESI) m/z=360 (M+H⁺).

Example 83

3-Amino-4-(1,4-diazepan-1-yl)-N-(2,5-dimethylphenyl)benzenesulfonamidehydrochloride (Scheme 5, Method 5)

The compound was prepared from 2,4-dimethylaniline; (crude yield 0.306g, yield analytical pure sample 0.015 g); ¹H NMR (CD₃OD) δ 7.33-7.28 (m,3H), 6.99-6.95 (m, 1H), 6.93-6.88 (m, 2H), 3.50-3.37 (m, 6H), 3.19-3.14(m, 2H), 2.22-2.13 (m, 5), 1.96 (s, 3H); MS (posES-FIA) m/z=375 (M+H⁺).

Example 84

3-Amino-N-(3-chlorophenyl)-4-(1,4-diazepan-1-yl)benzenesulfonamidehydrochloride (Scheme 5, Method 5)

The compound was prepared from 3-chloroaniline; (crude yield 0.610 g,yield analytical pure sample 0.015 g); ¹H NMR (CD₃OD) δ 7.25-7.24 (m,1H), 7.19-7.14 (m, 3H), 7.12-7.10 (m, 1H), 7.04-6.99 (m, 2H), 3.45-3.30(m, partly obscured by solvent signal, 6H), 3.15-3.11 (m, 2H), 2.14-2.08(m, 2H); MS (posES-FIA) m/z=381 (M+H⁺).

Example 85

3-Amino-4-(1,4-diazepan-1-yl)-N-(2-chlorophenyl)benzenesulfonamidehydrochloride (Scheme 5, Method 5)

The compound was prepared from 2-chloroaniline; (crude yield 0.506 g,yield analytical pure sample 0.020 g); ¹H NMR (CD₃OD) δ 7.55-7.50 (m,1H), 7.40-7.20 (m, 5H), 7.15-7.10 (m, 1H), 3.48-3.34 (m, 6H), 3.18-3.12(m, 2H), 2.20-2.10 (m, 2); MS (posEI) m/z=381 (M+H⁺).

Example 86

3-Amino-N-(2,4-dichlorophenyl)-4-(1,4-diazepan-1-yl)benzenesulfonamidehydrochloride (Scheme 5, Method 5)

The compound was prepared from 2,4-dichloroaniline; (crude yield 0.446g, yield analytical pure sample 0.080 g); ¹H NMR (CD₃OD) δ 7.53-7.50 (m,1H), 7.37-7.35 (m, 1H), 7.32-7.27 (m, 2H), 7.25-7.23 (m, 2H), 3.48-3.37(m, 6H), 3.18-3.12 (m, 2H), 2.20-2.10 (m, 2H); MS (posEI) m/z=415(M+H⁺).

Example 87

3-Amino-N-(2-methyl-5-chloro-phenyl)-4-(1,4diazepan-1-yl)benzenesulfonamidehydrochloride (Scheme 5, Method 5)

The compound was prepared from 2-methyl-5-chloroaniline; (crude yield0.516 g, yield analytical pure sample 0.015 g); ¹H NMR (CD₃OD) δ7.47-7.34 (m, 3H), 7.16-7.13 (m, 1H), 7.10 (-7.04 (m, 2H), 3.48-3.39 (m,6H), 3.20-3.15 (m, 2H), 2.21-2.14 (m, 2H); MS (posESI) m/z=395 (M+H⁺).

Example 88

3-Amino-N-(2-methyl-3-chloro-phenyl)-4-(1,4-diazepan-1-yl)benzenesulfonamidehydrochloride (Scheme 5, Method 5)

The compound was prepared from 2-methyl-3-chloroaniline; (crude yield0.537 g, yield analytical pure sample 0.22 g); ¹H NMR (CD₃OD) δ7.40-7.34 (m, 3H), 7.26-7.23 (m, 1H), 7.08-6.99 (m, 2H), 3.50-3.38 (m,6H), 3.20-3.16 (m, 2H), 2.21-2.14 (m, 2H) 2.11 (s, 3H); MS (posESI)m/z=395 (M+H⁺).

Example 89

3-Amino-N-(4-trifluoro-phenyl)-4-(1,4-diazepan-1-yl)benzenesulfonamidehydrochloride (Scheme 5, Method 5)

The compound was prepared from 4-trifluoroaniline; (crude yield 0.319 g,yield analytical pure sample 0.013 g); ¹H NMR (CD₃OD) δ 7.53-7.45 (m,2H), 7.27-7.22 (m, 3H), 7.13-7.08 (m, 2H), 3.43-3.30 (m, partly obscuredby solvent signal, 6H), 3.14-3.09 (m, 2H), 2.12-2.06 (m, 2H); MS(posESI) m/z=415 (M+H⁺).

Example 90

3-Amino-N-(4-fluorophenyl)-4-(1,4diazepan-1-yl)benzenesulfonamidehydrochloride (Scheme 5, Method 5)

The compound was prepared from 4-fluoroaniline; (crude yield 0.700 g,yield analytical pure sample 0.021 g); ¹H NMR (CD₃OD) δ 7.13-7.04 (m,4H), 7.03-6.98 (m, 1H), 6.97-6.91 (m, 2H), 3.45-3.30 (m, partly obscuredby solvent signal, 6H), 3.15-3.09 (m, 2H); MS (posEI) m/z=365 (M+H⁺).

Example 91

3-Amino-N-(2-fluorophenyl)-4-(1,4diazepan-1-yl)benzenesulfonamidehydrochloride (Scheme 5, Method 5)

The compound was prepared from 2-fluoroaniline; (crude yield 0.646 g,yield analytical pure sample 0.080 g); ¹H NMR (CD₃OD) δ 7.48-7.43 (m,1H), 7.36-7.34 (m, 1H), 7.36-7.27 (m, 1H), 7.25-7.21 (m, 1H), 7.15-7.05(m, 2H), 7.02-6.95 (m, 1H), 3.36-3.34 (m, 6H), 3.17-3.12 (m, 2H),2.16-2.10 (m, 2H); MS (posESI) m/z=365 (M+H⁺).

Example 92

3-Amino-4-(4-methyl-1,4-diazepan-1-yl)-N-phenylbenzenesulfonamide(Scheme 5, Method 5)

4-Chloro-3-nitrobenzenesulfonyl chloride (460 mg, 1.8 mmol) was added toa colorless solution of aniline (250 mg, 2.7 mmol) in CH₂Cl₂ (10 mL)followed by pyridine (0.80 mL, 10.0 mmol). The resulting orange solutionwas stirred at room temperature for 30 minutes, after which time themixture was concentrated under vacuum. Acidification with 2M aq. HClfollowed by extraction using EtOAc and drying with Na₂SO₄ followed byfiltration through a plug of silica, gave 500 mg (62%) of4-chloro-3-nitro-N-phenylbenzenesulfonamide ¹H NMR (CDCl₃) δ 8.30 (d,1H), 7.80 (dd, 2H), 7.55 (d, 1H), 7.20 (m, 5H). MS(negESI)m/z=311(M−H⁺). 1-Methylhomopiperazine (258 mg, 2.3 mmol) was added to asolution of 4-chloro-3-nitro-N-phenylbenzenesulfonamide obtained asabove (500 mg, 1.6 mmol) in CH₂Cl₂ (20 mL) followed by addition of K₂CO₃(310 mg, 2.3 mmol The reaction mixture was heated to reflux. After 2.5h, the solution was concentrated under vacuum. After adjusting to pH=6,the product was extracted using EtOAc to give, after drying with Na₂SO₄and concentration, 450 mg (72%) of4-(4-methyl-1,4-diazepan-1-yl)-3-nitro-N-phenylbenzenesulfonamide as anorange oil. ¹H NMR (CDCl₃) δ 8.15 (d, 1H), 7.60 (dd, 1H), 7.15 (m), 6.95(d, 1H), 3.45 (m, 2H), 3.30 (m, 2H), 2.75 (m, 2H), 2.60 (m, 2H), 2.35(s, 3H), 1.95 (m, 2H). MS (posESI) m/z=391(M+H⁺). To a solution of4-(4-methyl-1,4-diazepan-1-yl)-3-nitro-N-phenylbenzenesulfonamide (225mg, 0.58 mmol) in EtOH/THF (4/1, 25 mL) activated Raney-Ni (slurry inEtOH) and hydrazine monohydrate (142 μL, 2.9 mmol) were added. Afterstirring for 30 minutes at room temperature, the mixture was filteredand the yellow solution concentrated to give yellow oil. The oil wasdissolved in a mixture diethyl ether/EtOAc followed by addition ofexcess of HCl/ether. The resulting precipitate was filtered and washedwith ether to give, after drying under vacuum at 40° C., 88 mg (38%) of3-amino4-(4-methyl-1,4-diazepan-1-yl)-N-phenylbenzenesulfonamide as abeige solid. Mp 84-85° C. MS (posESI) m/z=361 (M+H⁺). ¹H NMR (MeOH-d3) δ7.85 (d, 2H), 7.60 (d, 1H), 7.15 (m, 5H), 3.50 (m, 7H), 3.15 (m, 2H),3.00 (s, 3H), 2.30 (m, 1H), 2.20 (m, 1H). Anal. (C₁₈H₂₄N₄SO₂.2HCl)C,H,N,S.

Example 93

4-(1,4-Diazepan-1-yl)-3-nitro-N-benzenesulfonamide hydrochloride (Scheme5, Method 5)

4-Chloro-3-nitro-N-benzenesulfonamide (1.52 g, 4.87 mmol), K₂CO₃ (1.01g, 7.3 mmol) and homopiperazine (0.585 g, 5.8 mmol) in CH₃CN (100 mL)was heated to 70° C. for 2 h. The mixture was filtered and the solventwas removed. Column chromatography (CH₂CL₂/MeOH/heptane 4:1:5×0.2% NH₃)gave 1.34 g of 4-(1,4-diazepan-1-yl)-3-nitro-N-benzenesulfonamidetogether with 0.152 g of the dialkylated product. The product (0.040 g)was transferred to its HCl-salt to give 0.038 g of the final product.Anal. (C₁₇H₂₁ClN₄O₄S×0.5H₂O) C, H, N.; MS (posESI) m/z=377.4 (M+H⁺).

Example 94

3-Amino-4-(1,4-diazepan-1-yl)-N-phenylbenzenesulfonamide hydrochloride(Scheme 5, Method 5)

4-(1,4-Diazepan-1-yl)-3-nitro-N-phenylbenzenesulfonamide (0.599 g, 1.6mmol) was dissolved in EtOH/THF (1:4). Hydrazine (0.398 mL, 8.0 mmol)and Raney-Ni (0.060 g) were added. After 1 h at room temperature thereaction was filtered through wet celite and the solvent was removed.The product was transferred to its HCl-salt by dissolving it in MeOH andadding HCl/ether. The solvent was removed and re-crystallized from(MeOH/ether) to give 0.537 g of a white solid. Anal.(C₁₇H₂₁ClN₄O₄S×1.5H2O) C, H, N.; MS (posESI) m/z=347.4 (M+H⁺).

Example 95

2-(1,4-diazepan-1-yl)-5-(4-morpholinylsulfonyl)aniline hydrochloride(Scheme 5, Method 5)

A suspension of homopiperazine (0.196 g, 1.95 mmol),4-[(4-chloro-3-nitrophenyl)sulfonyl]morpholine (0.461 g, 1.50 mmol) andK₂CO₃ (0.415 g, 3.00 mmol) in CH₃CN (10 mL) was stirred at 65° C. for 16h. CH₂CL₂ (10 mL) was added and the mixture was filtered andconcentrated. The crude product was purified by column chromatography onsilica using CHCl₃→CHCl₃/10% MeOH+0.4% aqueous ammonia to yield 0.546 gof the product as a yellow solid (yield 98%); ¹H NMR (CDCl₃) δ 8.13-8.07(m, 1H), 7.70-7.64 (m, 1H), 7.16-7.12 (m, 1H), 3.78-3.73 (m, 4H),3.55-3.49 (m, 2H), 3.44-3.36 (m, 2H), 3.19-3.13 (m, 2H), 3.06-3.00 (m,6H), 2.05-1.95 (m, 2H); ¹³C NMR (CDCl₃) δ 147.88, 137.39, 131.60,127.81, 122.66, 118.02, 66.23, 54.45, 51.02, 49.30, 48.27, 46.16, 29.46;MS (posES-FIA) m/z=372 (M+H⁺). To a solution of1-[4-(4-morpholinylsulfonyl)-2-nitrophenyl]-1,4-diazepane (0.445 g, 1.20mmol) in 30 mL of a 4:1 EtOH:THF solvent system was added Raney-Ni (100mg suspension in EtOH) followed by hydrazine monohydrate (300 mg, 6.00mmol). The mixture was stirred vigorously for 4 h and then filteredthrough celite that was pretreated with water. The filtrate wasconcentrated, and then re-dissolved in CH₃CN, concentrated again andfinally toluene was added and the mixture concentrated once more to givea brown solid. The crude product was purified by column chromatography(SiO₂, CHCl₃/MeOH/NH₃ 9:1:0.4%) to give 0.365 g (yield 89%) of the pureproduct as a solid. The free base was converted to its HCl salt; ¹H NMR(DMSO-d6) δ 9.34 (s, 2H), 7.23-7.16 (m, 2H), 7.04-6.98 (m, 1H),3.65-3.60 (m, 4H), 3.35-3.20 (m, 6H), 3.11-3.04 (m, 2H), 2.86-2.80 (m,4H), 2.09-1.99 (m,2); MS (posESI) m/z=341 (M+H⁺).

Intermediate 17

4-Chloro-N-(2-methoxy-phenyl)-3-nitrobenzenesulfonamide (Scheme 5,Method 5)

4-Chloro-3-nitrobenzenesulfonamide (1.73 g, 6.78 mmol) was dissolved inCH₂Cl₂ (7.0 mL). o-Anisidine (1.00 g, 8.13 mmol) was added dropwise atroom temperature, followed by a slow addition of pyridine (2.0 mL).After 16 h of continued stirring, the reaction mixture was diluted withEtOAc (50 mL) and washed with 1 M HCl (3×50 mL).

The organic phase was dried (MgSO₄) filtered and evaporated to a brownsolid, upon which re-crystallization from ethanol/water gave 2.22 g(95%) of the product as white crystals. ¹H NMR (CDCl₃) δ 8.20 (s, 1H),7.80 (dd, 1H), 7.56 (d, 1H), 7.53 (d, 1H), 7.13 (t, 1H), 6.96 (t, 1H),6.76 (d, 1H), 3.66 (s, 3H). The sulfonamide proton was not observed.

Intermediate 18

4-Chloro-3-nitro-N-phenyl-benzenesulfonamide (Scheme 5, Method 5)

Two portions of 4-Chloro-3-nitrobenzenesulfonamide (1.73 g, 6.78 mmol)were dissolved in CH₂Cl₂ (7.0 mL) in reaction flasks. Aniline (757 mg,8.13 mmol) was added drop-wise at room temperature, followed by slowadditions of pyridine (2.0 mL). After 16 h of continued stirring, thereaction mixtures were diluted with ethyl acetate (50 mL) and washedwith 1 M HCl (3×50 μL). The organic phases were dried (MgSO₄) andevaporated to brown solids, which upon re-crystallization fromethanol/water gave off-white solid of the product 2.04 g (96%): ¹H NMR(CDCl₃, 400 MHz) δ 8.24 (d, 1H), 7.80 (dd, 1H), 7.61 (d, 1H), 7.30 (t,2H), 7.20 (t, 1H), 7.09 (d, 2H), 6.79 (bs, 1H); MS (CI) 310.8 (M−H)⁻;Purity (HPLC, Hichrom 200×4.6 mm I.D.) >98%.

General procedure for reactions between4-Chloro-3-nitro-N-aryl-benzenesulfonamides and amines (R⁵) (Scheme 5,Method 5)

Solutions of Intermediate 17 (343 mg, 1.00 mmol) and Intermediate 12(313 mg, 1.00 mmol) in CH₃CN (5 mL) were treated with K₂CO₃ (276 mg,2.00 mmol) and amines (R⁵) (1.30 mmol) and heated to 80° C. for 16 h.The reaction mixtures were diluted with ethyl acetate (50 mL), washedwith saturated Na₂CO₃ (3×50 mL), dried (Na₂SO₄) and evaporated toproducts that could be used for the next step without purification.

Intermediate 19

N-(2-Methoxyphenyl)-4-(3-methyl-piperazin-1-yl)-3-nitrobenzenesulfonamide(Scheme 5, Method 5)

A solution of Intermediate 17 (343 mg, 1.00 mmol) and K₂CO₃ (276 mg,2.00 mmol) in CH₃CN (5 mL) was treated with 2-methylpiperazine (130 mg,1.30 mmol). After 16 h of stirring at 80° C., the reaction mixture wasdiluted with EtOAc (50 mL) and washed with saturated Na₂CO₃ (aq) (3×50mL). The organic phases were dried (Na₂SO₄) and evaporated to give 398mg of a yellow foam of the title compound (98%). ¹H NMR (CDCl₃) δ 8.16(d, 1H), 7.70 (dd, 1H), 7.50 (d, 1H), 7.06 (t, 1H), 6.97 (d, 1H), 6.91(t, 1H), 6.75 (d, 1H), 3.69 (s, 3H), 2.92-3.17 (m, 6H), 2.61 (t, 1H),1.05 (d, 3H). The sulfonamide and amine protons were not observed.

Intermediate 20

4-(Hexahydro-pyrrolo[1,2-a]pyrazin-2-yl)-N-(2-methoxyphenyl)-3-nitro-benzenesulfonamide(Scheme 5, Method 5)

A solution of Intermediate 17 (343 mg, 1.00 mmol) and K₂CO₃ (276 mg,2.00 mmol) in CH₃CN (5 mL) was treated withoctahydropyrrolo[1,2-a]pyrazine (164 mg, 1.30 mmol). After 16 h ofstirring at 80° C., the reaction mixture was diluted with EtOAc (50 mL)and washed with saturated Na₂CO₃ (3×50 mL). The organic phases weredried (Na₂SO₄) and evaporated to give 407 mg a yellow foam of the titlecompound (94%). ¹H NMR (CDCl₃) δ 8.16 (s, 1H), 7.70 (dd, 1H), 7.50 (d,1H), 7.06 (t, 1H), 7.00 (d, 1H), 6.91 (t, 1H), 6.75 (d, 1H), 3.69 (s,3H), 3.02-3.33 (m, 5H), 2.80 (t, 1H), 2.39 (t, 1H), 2.18-2.22 (m, 2H),1.76-1.85 (m, 3H), 1.37-1.40 (m, 1H). The sulfonamide and amine protonswere not observed.

Intermediate 21

3-Nitro-N-phenyl-4-piperazin-1-yl-benzenesulfonamide (Scheme 5, Method5)

The compound was prepared from Intermediate 18 and piperazine to give362 mg bright orange solid (100%): ¹H NMR (CDCl₃, 400 MHz) δ 8.16 (d,1H), 7.68 (d, 1H), 7.27 (t, 2H), 7.15 (t, 1H), 7.08 (d, 2H), 7.01 (d,1H), 3.13 (t, 4H), 2.98 (t, 4H); MS (CI) 362.8 (M+H)⁺361.2 (M−H)⁻;Purity (HPLC, Hichrom 200×4.6 mm I.D.) 91%.

Intermediate 22

4-(3-Methyl-piperazin-1-yl)-3-nitro-N-phenyl-benzenesulfonamide (Scheme5, Method 5)

The compound was prepared from Intermediate 18 and 1-methylpiperazine togive 373 mg orange-brown solid (99%): ¹H NMR (CDCl₃, 400 MHz) δ 8.17 (s,1H), 7.68 (d, 1H), 7.27 (t, 2H), 7.15 (t, 1H), 7.08 (d, 2H), 7.00 (d,1H), 3.14-3.22 (m, 2H), 2.97-3.06 (m, 4H), 2.64 (dd, 11H), 1.06 (d, 3H);MS (CI) 391.0 (M+H)⁺389.4 (M−H)⁻; Purity (HPLC, Hichrom 200×4.6 mm I.D.)>95%.

Intermediate 23

4-(4-Ethyl-piperazin-1-yl)-3-nitro-N-phenyl-benzenesulfonamide (Scheme5, Method 5)

The compound was prepared from Intermediate 18 and 1-ethylpiperazine togive 386 mg orange foam (99%): ¹H NMR (CDCl₃, 400 MHz) δ 8.19 (s, 1H),7.72 (dd, 1H), 7.31 (t, 2H), 7.18 (t, 1H), 7.11 (d, 2H), 7.04 (d, 1H),3.22 (bs, 4H), 2.60 (bs, 4H), 2.50 (q, 2H), 1.13(t, 3H); MS (CI) 377.0(M+H)⁺375.4 (M−H)⁻; Purity (HPLC, Hichrom 200×4.6 mm I.D.) >98%.

Intermediate 24

4-(Hexahydro-pyrrolo[1,2-a]pyrazin-2-yl)-3-nitro-N-phenyl-benzenesulfonamide (Scheme 5, Method 5)

The compound was prepared from Intermediate 18 andhexahydro-pyrrolo[1,2-a]2-pyrazine 372 mg orange foam (92%): ¹H NMR(CDCl₃, 400 MHz) δ 8.16 (s, 1H), 7.67 (d, 1H), 7.27 (t, 2H), 7.14 (t,1H), 7.08 (d, 2H), 7.03 (d, 1H), 3.02-3.35 (m, 5H), 2.83 (dd, 1H), 2.41(t, 1H), 2.18-2.25 (m, 2H), 1.72-1.85 (m, 3H), 1.32-1.43 (m, 1H); MS(CI) 403.2 (M⇄H)⁺401.0 (M−H)⁻; Purity (HPLC, Hichrom 200×4.6 mm I.D.)>95%.

Intermediate 25

4-(5-Methyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-3-nitro-N-phenyl-benzenesulfonamide(Scheme 5, Method 5)

The compound was prepared from Intermediate 18 and5-methyl-2,5-diaza-bicyclo[2.2.1]2-heptane to give 374 mg yellow solid(96%): ¹H NMR (CDCl₃, 400 MHz) δ 8.12 (d, 1H), 7.58 (d, 1H), 7.26 (t,2H), 7.13 (t, 1H), 7.07 (d, 2H), 6.76 (d, 1H), 4.24 (bs, 1H), 3.46-3.49(m, 2H), 2.88 (d, 1H), 2.80 (t, 2H); 2.33 (s, 3H), 1.89 (d, 1H), 1.53(bs, 1H); MS (CI) 389.0 (M+H)⁺387.0 (M−H)⁻; Purity (HPLC, Hichrom200×4.6 mm I.D.) >95%.

Intermediate 26

4-(trans-2,5-Dimethyl-piperazin-1-yl)-N-(2-methoxyphenyl)-3-nitro-benzenesulfonamide(Scheme 5, Method 5)

The compound was prepared from Intermediate 17 and4-(trans-2,5-dimethyl-piperazine to give 409 mg of yellow solid resulted(97%): ¹H NMR (CDCl₃, 400 MHz) δ 7.94 (d, 1H), 7.76 (dd, 1H), 7.50 (dd,1H), 7.28 (d, 1H), 7.10 (t, 1H), 6.93 (t, 1H), 6.73 (d, 1H), 2.93-3.08(m, 4H), 2.60 (dd, 1H), 2.31 (dd,1 H), 1.01 (d, 3H), 0.73 (d, 3H); MS(CI) 420.8 (M+H)⁺418.8 (M−H)⁻; Purity (HPLC, Hichrom 200×4.6 mm I.D.)>95%.

General procedure for reduction of the amino groups (Scheme 5, Method 5)

Solutions of the nitro compounds (0.25 mmol) in THF (10 mL) and methanol(2 mL) were treated with Raney-Ni (100 mg) and hydrazine monohydrate(120 μl, 2.5 mmol). After stirring at room temperature for 7 h, thesuspensions were filtered through celite and washed with ethyl acetateand ethanol. Evaporation with HCl in ether gave the products. Some ofthe products were without impurities, others had to be purified withHPLC ((YMC combiprep ODS-AQ, 50×20 mm I.D.).

Example 96

4-(1,4-Diazepan-1-yl)-N-phenyl-3-[(phenylsulfonyl)amino]benzenesulfonamidehydrochloride (Scheme 6, Method 6)

To a solution of tert-butyl4-[2-amino-4-(anilinosulfonyl)phenyl]-1,4-diazepane-1-carboxylate (0.268g g, 0.599 mmol), pyridine (338 μL, 4.19 mmol) and Et₃N (337 μL, 2.40mmol), in CH₂Cl₂ (8.0 mL) was added benzenesulfonyl chloride (153 μL,1.20 mmol) in CH₂Cl₂ (2 mL). The mixture was stirred at room temperaturefor 16 h. The reaction mixture was washed with saturated aqueous NaHCO₃,dried with Na₂SO₄, filtered and concentrated. The crude material wasdissolved in EtOH (5 mL) and KOH (0.134 g, 4.0 equiv.) was added. Thereaction was stirred at room temperature for 2 days. Water (5 mL) wasadded to the reaction mixture and most of the EtOH was evaporated undervacuum. The water phase was extracted with CH₂Cl₂ (3×20 mL). Thecombined organic phases were dried with Na₂SO₄, filtered andconcentrated. The crude boc-protected material was dissolved in MeOH,and ether saturated with HCl gas was added. The mixture was stirred for16 h and then concentrated to give 0.543 g of the crude product, whichwas purified by reversed phase preparative HPLC to give 0.153 g of thepure product as the acetic acid salt which was converted to theHCl-salt: ¹H NMR (DMSO-d6) δ 10.25 (s, 1H), 9.09 (br s, 2H), 7.68-7.58(m, 4H), 7.54-7.48 (m, 2H), 7.46-7.42 (m, 1H), 7.23-7.16 (m, 3H),7.05-6.28 (m, 3H), 3.35-3.15 (m, partly obscured by solvent signal HDO,6H), 2.81-2.75 (m, 2H), 1.92-1.85 (m, 2H); MS (posES-FIA) m/z=487(M+H⁺).

Example 97

4-(1,4-Diazepan-1-yl)-N-phenyl-3-[(methylsulfonyl)amino]benzenesulfonamidehydrochloride (Scheme 6, Method 6)

A mixture of tert-butyl4-[2-amino-4-(anilinosulfonyl)phenyl]-1,4-diazepane-1-carboxylate (176mg, 0.39 mmol), methylsulfonyl chloride (0.040 mL, 0.47 mmol) andpyridine (0.285 mL, 3.51 mmol) in CH₂CL₂ (5 mL) was stirred at roomtemperature overnight. The reaction mixture was quenched with NaHCO₃ aq(3×30 mL). The organic phase was separated, dried (MgSO₄) and filtered.The volatiles were evaporated followed by purification of the oilyresidue by chromatography (SiO₂, hexane/EtOAc 4:1) to give 110 mg oftert-butyl4-{4-(anilinosulfonyl)-2-[(methylsulfonyl)amino]phenyl}-1,4-diazepane-1-carboxylate(yield 58%). ¹H NMR (CDCl₃) δ 7.90-7.85 (m, 1H), 7.50-7.43 (m, 1H),7.30-7.24 (m, 2H), 7.20-7.08 (m, 4H), 6.84-6.79 (m, 1H), 3.65-3.51 (m,4H), 3.12-3.06 (m, 1H), 3.04-2.96 (m, 6H), 2.04-1.91 (m, 2H), 1.49 (s,3H); MS (posEI-DIP) m/z=524 (M+H⁺). tert-Butyl4-{4-(anilinosulfonyl)-2-[(methylsulfonyl)amino]phenyl}-1,4-diazepane-1-carboxylate(0.077 g, 0.147 mmol) was dissolved in MeOH, and ether saturated withHCl gas was added. The mixture was stirred at room temperature for 4 hand then concentrated. The crude solid was dissolved in a small amountof MeOH, and ether was added. The precipitate was collected and dried togive 30 mg of the pure product as the HCl salt (yield 48%): ¹H NMR(DMSO-d6) δ 7.72-7.70 (m, 1H), 7.46-7.42 (m, 1H), 7.25-7.20 (m, 3H),7.14-7.09 (m, 2H), 7.03-6.99 (m, 1H), 3.45-3.15 (m, partly obscured bysolvent signal, HDO, 6H), 2.96 (s, 3H), 2.02-1.95 (m, 2H); MS(posES-FIA) m/z=425 (M+H⁺).

Example 98

3-Amino-N-(3-chlorophenyl)-4-(4-methyl-1-1-piperazinyl)benzenesulfonamidehydrochloride (Scheme 5, Method 5)

A mixture of 4-chloro-3-nitrobenzenesulfonylchloride (1 g, 3.9 mmol),3-chloroaniline (0.5 mL, 4.7 mmol) and pyridine (1.6 mL) in CH₂Cl₂ (2mL) was stirred at room temperature. The reaction was quenched withNaHCO₃ (sat aq solution, 30 mL×3). The organic phase was separated,dried (MgSO₄), and filtered. The volatiles were evaporated and theresidue was purified by column chromatography (SiO₂, pentane:EtOAc, 4:1)to give 4-chloro-N-(3-chlorophenyl)-3-nitrobenzenesulfonamide; MS(posESI) m/z=349.2 (M+H⁺). ¹H NMR (CDCl₃) δ 7.00-7.40 (m, 3H), 7.60-7.90(m, 3H), 8.70 (bs, 1H).4-Chloro-N-(3-chlorophenyl)-3-nitrobenzenesulfonamide (0.45 g, 1.3mmol), N-methylpiperazine (0.191 mL, 1.73 mmol) and K₂CO₃ (359 mg, 2.6mmol) in CH₃CN (2.5 mL) as the filtrated was concentrated to give aresidue which was purified by column (SiO₂, CHCl₃:MeOH: NH₃ 9:1:0.4%) togive 420 mg ofN-(3-chlorophenyl)-4-(4-methyl-1-piperazinyl)-3-nitrobenzenesulfonamide(85%). Purity >95% according to HPLC analysis. The compound wasdissolved in THF (1 mL) and ethanol (5 mL) was added. The solution wastreated with Raney-Ni (50 mg) and hydrazine monohydrate (0.05 mL)overnight. The Raney-Ni was filtered (celite pad), the volatiles wereevaporated and the residue was purified by column chromatography (SiO₂,CHCl₃:MeOH: NH₃ 9:1:0.4%). The product was isolated as hydrochloridesalt by treatment with HCl gas in diethyl ether to yield 170 mg of finalproduct (32%).

¹H NMR (DMSO-d6) δ 7.25 (appt, 1H), 7.15-7.17 (m, 1H), 7.10-6.12 (m,1H), 7.00-7.10 (m, 4H); 3.43-3.45 (m, 2H), 3.22-3.24 (m, 4H), 2.96-3.01(m, 2H), 2.77-2.78 (s, 3H); MS (posESI) m/z=380.1(M+H⁺).

Example 99

3-Amino-N-(2-methoxyphenyl)-4-(4-methyl-1-piperazinyl)benzenesulfonamidehydrochloride (Scheme 5, Method 5)

The compound was prepared from 4-chloro-3-nitrobenzenesulfonylchloride(1 g, 3.9 mmol), 2-methoxyaniline (0.53 mL, 4.7 mmol) and pyridine (1.6mL) in CH₂Cl₂ (2 mL).4-Chloro-N-(2-methoxyphenyl)-3-nitrobenzenesulfonamide (0.345 mg) wasreacted with N-methylpiperazine (0.144 mL) to affordN-(2-methoxyphenyl)4-(4-methyl-1-piperazinyl)-3-nitrobenzenesulfonamidewhich was treated with Raney-Ni and hydrazine monohydrate. The finalproduct was isolated as its HCl salt ¹H NMR (DMSO-d6) δ 7.185 (dd, 1H),7.08 (dt, 1H), 6.975 (d, 1H),6.91-6.94 (m, 2H); 6.84 (dt, 1H), 3.56 (s,3H), 3.42-3.47 (m, 2H), 3.22-3.24 (m, 2H), 2.95 (bt, 2H), 2.79 (bs, 3H);MS (posESI) m/z=376.2 (M+H⁺).

Example 100

3-Amino-N-(2-methoxyphenyl)-4-(1-piperazinyl)benzenesulfonamidehydrochloride (Scheme 5, Method 5)

The compound was prepared from 4-chloro-3-nitrobenzenesulfonyl chloride(1 g, 3.9 mmol), 2-methoxyaniline (0.53 mL, 4.7 mmol) and pyridine (1.6mL) in CH₂CL₂ (2 mL).4-Chloro-N-(2-methoxyphenyl)-3-nitrobenzenesulfonamide (0.345 g) wasreacted with piperazine (0.111 g) to affordN-(2-methoxyphenyl)-4-(piperazinyl)-3-nitrobenzenesulfonamide. This wasthen treated with Raney-Ni and hydrazine monohydrate. The final productwas isolated as its HCl salt. ¹H NMR (DMSO-d6) δ 7.18-7.20 (m, 1H),7.08-7.10 (m, 2H), 6.93-6.96 (m, 1H), 6.91-6.93 (m, 2H); 6.84 (dt, 1H),3.56 (s, 3H), 3.22-3.27 (m, 4H), 3.00-3.02 (m, 4H); MS (posESI)m/z=362.1 (M+H⁺).

Example 101

3-Amino-N-(2-methoxyphenyl)-4-(3-methyl-piperazin-1-yl)-benzenesulfonamide(Scheme 5, Method 5)

The compound was prepared fromN-(2-methoxyphenyl)4-(3-methylpiperazin-1-yl)-3-nitro-benzenesulfonamideto give 90 mg of the title compound (96%). ¹H NMR (CDCl₃) δ 7.44 (d,1H), 7.11 (d, 1H), 7.10 (d, 1H), 6.97 (t, 1H), 6.85 (d, 1H), 6.84 (t,1H), 6.72 (d, 1H), 3.97 (bs, 2H), 3.62 (s, 3H), 2.91-3.06 (m, 5H), 2.56(t, 1H), 2.23 (t, 1H), 1.41 (s, 1H), 1.05 (d, 3H). The sulfonamideprotons were not observed. ¹³C NMR (CDCl₃) δ 149.4, 143.1, 141.4, 134.6,125.4, 124.4, 121.0, 120.4, 119.2, 117.7, 113.2, 110.5, 55.6, 51.1,50.8, 46.3, 30.3, 19.6. MS (CI neg) 375 (M−H⁺), (CI pos) 377 (M+H⁺).

Example 102

3-Amino-4-(hexahydro-pyrrolo[1,2-a]pyrazin-2-yl)-N-(2-methoxyphenyl)-benzenesulfonamide(Scheme 5, Method 5)

The compound was prepared from4-(hexahydro-pyrrolo[1,2-a]pyrazin-2-yl)-N-(2-methoxyphenyl)-3-nitrobenzenesulfonamideto give 97 mg of the title compound (96%). ¹H NMR (CDCl₃) δ 7.44 (d,1H), 7.12 (d, 1H), 7.11 (d, 1H), 6.97 (t, 1H), 6.90 (d, 1H), 6.84 (t,1H), 6.72 (d, 1H), 3.96 (bs, 2H), 3.62 (s, 3H), 3.19 (d, 1H), 3.09 (appt, 3H), 2.76 (t, 1H), 2.45 (t, 1H), 2.31-2.38 (m, 1H), 2.10-2.21 (m,2H), 1.72-1.87 (m, 3H), 1.21 (t, 1H). The sulfonamide protons were notobserved. ¹³C NMR (CDCl₃) δ 149.4, 143.1, 141.4, 134.4, 125.4, 124.7,121.0, 120.5, 119.5, 117.7, 113.2, 110.5, 55.6, 55.0, 53.3, 52.0, 49.7,30.3, 27.3, 21.2. MS (CI neg) 401 (M−H⁺).

Example 103

3-Amino-N-phenyl-4-piperazin-1-yl-benzenesulfonamide hydrochloride(Scheme 5, Method 5)

The compound was prepared from N-phenyl-4-piperazin-1-yl-3-nitrobenzenesulfonamide to give 15 mg yellow solid (18%): ¹H NMR (MeOD, 400MHz) δ 7.57-7.61 (m, 2H), 7.40 (d, 1H), 7.23 (t, 2H), 7.13 (d, 2H), 7.07(t, 1H), 3.45 (t, 4H), 3.20 (t, 4H); MS (CI) 333.0 (M+H)⁺331.4 (M−H)⁻;Purity (HPLC, Hichrom 200×4.6 mm I.D.) 96%.

Example 104

3-Amino-4-(3-methyl-piperazin-1-yl)-N-phenyl-benzenesulfonamidehydrochloride (Scheme 5, Method 5)

The compound was prepared from4-(3-methyl-piperazin-1-yl)-N-3-nitrophenyl-benzenesulfonamide to give33 mg white solid (35%): ¹H NMR (MeOD, 400 MHz) δ 7.57-7.62 (m, 2H),7.35-7.41 (m, 1H), 7.12 (t, 2H), 7.02 (d, 2H), 6.97 (t, 1H), 3.53-3.58(m, 1H), 3.31-3.40 (m, 2H), 3.16 (t, 2H), 2.99-3.05 (m, 1H), 2.79 (t,1H), 1.27 (d, 3H); MS (CI) 346.8 (M+H)⁺345.4 (M−H)⁻; Purity (HPLC,Hichrom 200×4.6 mm I.D.) 100%.

Example 105

3-Amino-4-(4-ethyl-piperazin-1-yl)-N-phenyl-benzenesulfonamidehydrochloride (Scheme 5, Method 5)

The compound was prepared from3-Amino-4-(4-ethyl-piperazin-1-yl)-N-phenyl-benzenesulfonamide to give32 mg white solid (33%): ¹H NMR (MeOD, 400 MHz) δ 7.52-7.57 (m, 2H),7.36 (d, 1H), 7.12 (t, 2H), 7.01 (d, 2H), 6.96 (t, 1H), 3.56 (d, 2H),3.26 (t, 2H), 3.17-3.23 (m, 4H), 3.09 (t, 2H), 1.31 (t, 3H); MS (CI)361.0 (M+H)⁺359.4 (M−H)⁻; Purity (HPLC, Hichrom 200×4.6 mm I.D.) 96%.

Example 106

3-Amino-4-(hexahydro-pyrrolo[1,2-a]pyrazin-2-yl)-N-phenyl-benzenesulfonamidehydrochloride (Scheme 5, Method 5)

The compound was prepared from4-(hexahydro-pyrrolo[1,2-a]pyrazin-2-yl)-N-phenyl-3-nitro-benzenesulfonamideto give 50 mg white solid (49%): ¹H NMR (MeOD, 400 MHz) δ 7.63-7.69 (m,2H), 7.47-7.52 (m, 1H), 7.23 (t, 2H), 7.13 (d, 2H), 7.08 (t, 1H),3.08-3.78 (m, 8H), 2.12-2-35 (m, 4H), 1.79-1.88 (m, 1H); MS (CI) 372.8(M+H)⁺371.4 (M−J)⁻; Purity (HPLC, Hichrom 200×4.6 mm I.D.) 100%.

Example 107

3-Amino-4-(5-methyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-N-phenyl-benzenesulfonamidehydrochloride (Scheme 5, Method 5)

The compound was prepared from4-(5-methyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-N-phenyl-3-nitrobenzenesulfonamide to give 40 mg red solid (40%): ¹H NMR (MeOD, 400MHz, major conformer at 300 K) δ 7.49-7.56 (m, 2H), 7.09-7.15 (m, 3H),6.99-7.05 (m, 2H), 6.95 (t, 1H), 4.39 (bs, 1H), 4.30 (bs, 1H), 3.89 (d,1H), 3.56 (bs, 2H), 3.09 )d, 1H), 2.88 (s, 3H), 2.34 (d, 1H), 2.20 (d,1H); MS (CI) 359.0 (M+H)⁺357.4 (M−H)⁻; Purity (HPLC Hichrom 200×4.6 mmI.D.) 93%.

Example 108

3-Amino-4-(trans-2,5-dimethyl-piperazin-1-yl)-N-(2-methoxy-phenyl)-benzenesulfonamidehydrochloride (Scheme 5, Method 5)

The compound was prepared from4-(trans-2,5-dimethyl-piperazin-1-yl)-N-(2-methoxy-phenyl)-3-nitrobenzenesulfonamideto give 60 mg white solid (61%): ¹H NMR (MeOD, 400 MHz) δ 7.54-7.58 (m,2H), 7.45 (d, 1H), 7.32 (d, 1H), 7.02 (t, 1H), 6.81 (d, 1H), 6.76 (t,1H), 3.54-3.57 (m, 1H), 3.47 (s, 3H), 3.37 (d, 1H), 3.30-3.34 (m, 1H),3.01 (t, 2H), 2.71 (t, 1H), 1.23 (d, 3H), 0.77 (d, 3H); MS (CI) 390.8(M+H)⁺389.4 (M−H)⁻; Purity (HPLC, Hichrom 200×4.6 mm I.D.) 96%.

Example 109

2-(3-Amino-4-[1,4]diazepan-1-yl-benzenesulfonyl)-benzamide diacetic acid(Scheme 5, Method 5)

The compound was prepared from 2-amino-benzamide,4-chloro-3-nitro-benzenesulfonyl chloride and 1,4]diazepane-1-carboxylicacid tert-butyl to give (1%) as an oil. ¹H NMR (CD₃OD) δ 7.68-7.57 (m,2H), 7.43-7.36 (m, 1H), 7.17-7.15 (m, 1H), 7.10-7.02 (m, 3H), 3.44-3.25(m, 6H), 3.12-3.05 (m, 2H), 2.14-2.02 (m, 2H); MS m/z (M+1) 3.90.

Example 110

4-[4-(3-Fluoro-2-methoxy-phenylsulfamoyl)-2-amino-phenyl]-[1,4]diazepaneditrifluoroacetic acid (Scheme 5, Method 5)

The compound was prepared from 3-fluoro-2-methoxyaniline,4-chloro-3-nitro-benzenesulfonyl chloride and 1,4]diazepane-1-carboxylicacid tert-butyl ester to give (43%) as a solid. ¹H NMR (DMSO) δ 9.70 (s,1H), 8.79 (br s, 2H), 7.17-6.87 (m, 6H), 3.53 (s, 3H), 3.32-3.13 (m,6H), 2.99-2.91 (m, 2H), 2.01-1.89 (m, 2H); MS m/z (M+1) 395.

Example 111

2-[1,4]Diazepan-1-yl-5-(3,4-dihydro-1H-isoquinoline-2-sulfonyl)-anilinedihydrochloride (Scheme 5, Method 5)

The compound was prepared from 1,2,3,4-tetrahydro-isoquinoline,4-chloro-3-nitro-benzenesulfonyl chloride and 1,4]diazepane-1-carboxylicacid tert-butyl ester to give (93%) as a white solid. ¹H NMR (DMSO) δ9.28 (s, 2 H), 7.12 (m, 7 H), 4.12 (s, 2 H), 3.20 (m, 8 H), 3.02 (t,J=5.81 Hz, 2 H), 2.86 (t, J=6.07 Hz, 2 H), 2.00 (m, 2 H); MS m/z 387(M+1).

Example 112

4-[4-(3,4-Dihydro-2H-quinoline-1-sulfonyl)-2-amino-phenyl]-[1,4]diazepaneditrifluoroacetic acid (Scheme 5, Method 5)

The compound was prepared from 1,2,3,4-tetrahydro-quinoline4-chloro-3-nitro-benzenesulfonyl chloride and[1,4]diazepane-1-carboxylic acid tert-butyl ester (430 μl, 2.2 mmol) togive (63%) as a solid. ¹H NMR (CD₃OD) δ 7.69-7.62 (m, 1H), 7.16-6.98 (m,5H), 6.94-6.89 (m, 1H), 3.78-3.71 (m, 2H), 3.46-3.27 (m, 6H), 3.13-3.06(m, 2H), 2.48-2.40 (m, 2H), 2.16-2.05 (m, 2H), 1.69-1.58 (m, 2H); MS m/z(M+1) 387.

Legend to Scheme 2:

i: Py, CH₂CL₂; ii: K₂CO₃, CH₃CN, diamine (i. e. homopiperazine); iii:(BOC)₂O, THF, NaOH; iv: Raney-Ni, Hydrazine monohydrate, THF/EtOH; v:sulfonylchloride (Y—SO₂—Cl), Py, Et₃N, CH₂CL₂; vi: HCl ether/MeOH

Intermediate 27

tert-Butyl-4-[4-(anilinosulfonyl)-2-nitrophenyl]-1,4-diazepane-1-carboxylate(Scheme 6, Method 6)

Di-tert-butyl dicarbonate (0.921 g, 4.22 mmol) in THF (20.0 mL) wasadded to a solution of4-(1,4-diazepan-1-yl)-3-nitro-N-phenylbenzenesulfonamide (0.530 g, 1.40mmol) and NaOH (0.140 g, 3.50 mmol) dissolved in THF:water (30 mL, 1:1).The solution was stirred at room temperature for 3 h. The mixture wasneutralized with 5 N HCl and then the THF was removed under vacuum. Theaqueous phase was extracted with CHCl₃ (2×50 mL) and the combinedorganic layers were dried over Na₂SO₄, filtered and concentrated.Purification via flash column chromatography (SiO₂, usingCHCl₃/MeOH/9.75:0.25) gave a solid, which was triturated withEtOAc/pentane to give 0.605 g (90%) of the pure product. ¹H NMR(DMSO-d6) δ 9.84 (br s, 1H), 8.01-7.98 (m, 1H), 7.70-7.65 (m, 1H),7.32-7.28 (m,1H), 7.26-7.20 (m, 2H), 7.13-7.08 (m, 2H), 7.07-7.02 (m,1H), 3.61-3.48 (m, 4 H), 3.39-3.33 (m, 2H), 3.23-3.15 (m, 2H), 1.85-1.76(m, 2H), 1.18 (s, 9H); MS (posESI-FIA) m/z=477 (M+H⁺).tert-Butyl-4-[2-nitro-4-(anilinosulfonyl)phenyl]-1,4-diazepane-1-carboxylatewas reduced to the final product by treatment with Raney-Ni andhydrazine monohydrate using method C to yield 0.477 g (91%) of the freebase; ¹H NMR (DMSO-d6) δ 9.81 (s, 1H), 7.24-7.18 (m, 2H), 7.13-7.08 (m,3H), 7.02-6.92 (m, 3H), 4.99 (m, 2H), 3.53-3.45 (m, 4H), 3.02-2.94 (m,4H), 1.86-1.79 (m, 2H), 1.42 (9H); MS (posESI-FIA) m/z=447 (M+H⁺).

Intermediate 28

N-Naphthalen-1-yl-3-nitro-4-piperazin-1-yl-benzenesulfonamide,hydrochloride

4-Chloro-3-nitrobenzenesulphonyl chloride (0.992 g, 3.87 mmol) was addedto a solution of naphthalen-1-ylamine (0.665 g, 4.64 mmol) and pyridine(3.1 mL, 38.7 mmol) dissolved in DCM (5 mL). The solution was stirred atroom temperature for 2 days and the volatiles were evaporated. The crudemixture was dissolved in EtOAc and the organic phase was washed with 1 NHCl, dried with MgSO₄, filtered and concentrated to give 1.1 g ofnaphthalen-1-yl-3-nitro-4-chloro-benzenesulphonamide.Naphthalen-1-yl-3-nitro-4-chloro-benzenesulphonamide was dissolved inCH₃CN (10 mL) and piperazine (0.683 g, 7.93 mmol) was added. The mixturewas stirred at 65° C. for 16 hours. The mixture was concentrated and thecrude product was purified by flash chromatography on silica usingDCM→DCM/MeOH (10%)+aqueous NH₃ (0.4 as eluent to give 0.531 g of thefree base which was converted to its HCl-salt.

¹H NMR (DMSO-hd6) δ 10.36 (brs, 1H), 9.33 (brs, 2H), 8.12 (D, J=2.1 Hz,1H), 8.05-7.99 (m, 1H), 7.94-7.88 (m, 1H), 7.85-7.72 (m, 2H), 7.55-7.38(m, 4H), 7.22-7.16 (m, 1H), 3.40-3.30 (m, obscured by solvent signal,4H), 3.24-3.12 (m, 4H); MS (posES-FIA) m/z=413 (M+H).

Example 113

3-Amino-2-chloro-N-naphthalen-1-yl-4-piperazin-1-yl-benzenesulfonamide,hydrochloride

To a solution of N-naphthalen-1-yl-3-nitro-4-piperazin-1-yl-benzenesulfonamide (0.4602 g, 11.2 mmol) in 40 mL of a 4:1EtOH:THF solvent system was added Raney-Ni (˜1.0 mL suspension in EtOH)followed by hydrazine mono-hydrate (2.80 g, 56.0 mmol). The mixture wasstirred vigorously for 3 hours and then filtered through celite. Thefiltrate was concentrated and the crude product was triturated withMeOHiether. The product was converted to its HCl-salt. Yield (90%) asthe free base. An aliquot was purified by preparative LC/MS.

¹H NMR (DMSO-d6) δ 9.20-8.90 (brs 2H), 8.25-8.21 (m, 1H), 7.90-7.86 (m,(m, 1H), 7.74 (d, J=8.48 Hz, 1H), 7.52-7.46 (m, 2H), 7.39-7.35 (m, 1H),7.24-7.21 (m, 1H), 7.10 (d, J=8.48 Hz, 1H), 6.91 (m, d, J=8.48 Hz, 1H),3.32-3.25 (m, obscured by solvent signal, 4H), 3.03-2.98 (m, 4H); MS(posES-FIA) m/z=383.

Biological Tests

The ability of a compound according to the invention to bind a 5-HT₆receptor, and to be pharmaceutically useful, can be determined using invivo and in vitro assays known in the art.

(a) 5-HT₆ Intrinsic Activity Assay

Antagonists to the 5-HT6 receptor were characterized by measuringinhibition of 5-HT induced increase in cAMP in HEK 293 cells expressingthe human 5-HT₆ receptor (see Boess et al. (1997) Neuropharmacology 36:713-720). Briefly, HEK293/5-HT₆ cells were seeded in polylysine coated96-well plates at a density of 25,000/well and grown in DMEM (Dulbecco'sModified Eagle Medium) (without phenol-red) containing 5% dialyzedFoetal Bovine Serum for 48 h at 37° C. in a 5% CO₂ incubator. The mediumwas then aspirated and replaced by 0.1 ml assay medium (Hanks BalanceSalt Solution containing 20 mM HEPES, 1.5 mM isobutylmethylxanthine and1 mg/ml bovine serum albumin). After addition of test substances, 50 μldissolved in assay medium, the cells were incubated for 10 min at 37° C.in a 5% CO₂ incubator. The medium was again aspirated and the cAMPcontent was determined using a radioactive cAMP kit (Amersham PharmaciaBiotech, BIOTRAK RPA559). The potency of antagonists was quantified bydetermining the concentration that caused 50% inhibition of 5-HT (at[5-HT]=8 times EC₅₀) evoked increase in cAMP, using the formulaK_(i,eff)=IC₅₀/(1+[5HT]/EC₅₀).

The compounds in accordance with the invention have a selective affinityto 5-HT₆ receptors with K_(i) values between 1 nM and 5 μM and theyantagonized the 5-HT indiced increase of cAMP. There is correlationbetween the K_(i) binding and the K_(i,efficacy). Moreover, thecompounds show good selectivity (>100 fold) against 5-HT_(2a),5-HT_(2b), 5-HT_(2c), 5-HT_(1a), 5-HT_(1b).

(b) In vivo Assay of Reduction Of Food Intake

For a review on serotonin and food intake, see Blundell, J. E. andHalford, J. C. G. (1998) Serotonin and Appetite Regulation. Implicationsfor the Pharmacological Treatment of Obesity. CNS Drugs 9:473-495.

Obese (ob/ob) mouse is selected as the primary animal model forscreening as this mutant mouse consumes high amounts of food resultingin a high signal to noise ratio. To further substantiate and compareefficacy data, the effect of the compounds on food consumption is alsostudied in wild type (C57BL/6J) mice. The amount of food consumed during15 hours of infusion of compounds is recorded.

Male mice (obese C57BL/6JBom-Lep^(ob) and lean wild-type C57B1/6JBom;Bomholtsgaard, Denmark) 8-9 weeks with an average body weight of 50 g(obese) and 25 g (lean) are used in all the studies. The animals arehoused singly in cages at 23±1° C., 40-60% humidity and have free accessto water and standard laboratory chow. The 12/12-h light/dark cycle isset to lights off at 5 p.m. The animals are conditioned for at least oneweek before start of study.

The test compounds are dissolved in solvents suitable for each specificcompound such as cyclodextrin, cyclodextrin/methane sulfonic acid,polyethylene glycol/methane sulfonic acid, saline. Fresh solutions aremade for each study. Doses of 30, 50 and 100 mg kg⁻¹day⁻¹ are used. Thepurity of the test compounds is of analytical grade.

The animals are weighed at the start of the study and randomized basedon body weight. Alzet osmotic minipumps (Model 2001D; infusion rate 8μl/h) are used and loaded essentially as recommended by the Alzettechnical information manual (Alza Scientific Products, 1997; Teeuwesand Yam, 1976). Continuous subcutaneous infusion with 24 hours durationis used. The minipumps are either filled with different concentrationsof test compounds dissolved in vehicle or with only vehicle solution andmaintained in vehicle pre-warmed to 37° C. (approx. 1 h). The minipumpsare implanted subcutaneously in the neck/back region under short actinganesthesia (metofane/enflurane). This surgical procedure lastsapproximately 5 min. It takes about 3 h to reach steady state deliveryof the compound.

The weight of the food pellets are measured at 5 p.m. and at 8 p. m. fortwo days before (baseline) and one day after the implantation of theosmotic minipumps. The weigh-in is performed with a computer assistedMettler Toledo PR 5002 balance. Occasional spillage is corrected for. Atthe end of the study the animals are killed by neck dislocation andtrunk blood sampled for later analysis of plasma drug concentrations.

The plasma sample proteins are precipitated with methanol, centrifugedand the supernatant is transferred to HPLC vials and injected into theliquid chromatography /mass spectrometric system. The mass spectrometeris set for electrospray positive ion mode and Multiple ReactionMonitoring (MRM with the transition m/z 316

221).

A linear regression analysis of the standards forced through the originis used to calculate the concentrations of the unknown samples.

Food consumption for 15 hours is measured for the three consecutive daysand the percentage of basal level values is derived for each animal fromthe day before and after treatment. The values are expressed as mean ±SDand ±SEM from eight animals per dose group. Statistical evaluation isperformed by Kruskal-Wallis one-way ANOVA using the percent basalvalues. If statistical significance is reached at the level of p<0.05,Mann-Whitney U-test for statistical comparison between control andtreatment groups is performed.

The compounds according to the invention show an effect in the range of50-150 mg/kg.

TABLE VII Reduction of Food Intake (%) EXAMPLE Dose (mg/Kg) poadministration 27 50 28 29 100 60

1. A method for the treatment of type II diabetes, the method comprisingadministering to a subject in need thereof an effective amount of acompound of formula (I)

or a pharmaceutically acceptable salt thereof, wherein X is

R¹ and R³ are independently (a) H (b) C₁₋₆ alkyl, (c) C₁₋₆ alkoxy, (d)straight or branched C₁₋₆ hydroxyalkyl, (e) straight or branched C₁₋₆alkylhalides; or (f) a group Ar; Ar is (a) phenyl, (b) 1-naphthyl, (c)2-naphthyl, (d) benzyl, (e) cinnamoyl, (f) a 5 to 7-membered, partiallyor completely saturated, heterocyclic ring containing 1 to 4heteroatoms, selected from oxygen, nitrogen and sulfur, or (g) abicyclic ring system consisting of two heterocyclic rings as definedunder (f), or a bicyclic ring system consisting of one benzene ring andone heterocyclic ring as defined under (f); alternatively, R¹ and R³ arelinked to form a group (CH₂)₂O, (CH₂)₄O, or (CH₂)₃₋₅ in formula (Ib);optionally, the group Ar is substituted with (a) Y, or (b) a 5 to7-membered, partially or completely saturated, heterocyclic ring eachcontaining 1 to 4 heteroatoms selected from oxygen, nitrogen or sulfur;Y is (a) H, (b) halogen, (c) C₁₋₆ alkyl, (d) CF₃, (e) hydroxy, (f) C₁₋₆alkoxy, (g) C₁₋₄ alkenyl; (h) phenyl; (i) phenoxy, (j) benzyloxy, (k)benzoyl, (l) OCF₃, (m) CN, (n) straight or branched C₁₋₆ hydroxyalkyl,(o) straight or branched C₁₋₆ alkylhalides, (p) NH₂, (q) NHR⁶, (r)NR⁶R⁷, (s) NO₂, (t) —CONR⁶R⁷, (u) NHSO₂R⁶, (v) NR⁶COR⁷, (x) SO₂NR⁶R⁷,(z) —C(═O)R⁶, (aa) —CO₂R⁶, or (ab) S(O)_(n)R⁶; wherein n is 0, 1, 2 or3; R² and R⁴ are independently: (a) —SO₂R¹, (b) H, (c) C₁₋₆ alkyl, (d)C₁-C₃ alkenyl, (e) C₁-C₃ alkylaryl, (f) Ar as defined above for R¹, (g)—C(═O)R⁶, (h) —C(O)NR⁶R⁷, (i) —C(S)NR⁶R⁷, (j) —CO₂R⁶; (k) —C(S)R⁶; (l)straight or branched C₁₋₆ hydroxyalkyl, or (m) straight or branched C₁₋₆alkylhalides; alternatively, R² and R⁴ are linked to form a group(CH₂)₂O, (CH₂)₄O, or (CH₂)₃₋₅ in formula (Ia); R⁵ is selected from thegroup consisting of the following chemical groups:

R⁶ and R⁷ are independently (a) H, (b) C₁₋₆ alkyl, (c) C₃₋₇ cycloalkyl,or (d) Ar, as defined above for R¹; alternatively, R⁶ and R⁷ are linkedto form a group (CH₂)₂O, (CH₂)₄O or (CH₂)₃₋₅; R⁸is (a) H, or (b) C₁₋₆alkyl.
 2. The method of claim 1, wherein: R¹ is a group Ar; Ar is (a)phenyl, (b) 1-naphthyl, (c) 2-naphthyl, or (f) a 5 to 7-membered,partially or completely saturated, heterocyclic ring containing 1 to 4heteroatoms, selected from oxygen, nitrogen and sulfur; the group Ar issubstituted with Y, wherein Y is (a) H, (b) halogen, (c) C₁₋₆ alkyl, (d)CF₃, (f) C₁₋₆ alkoxy, (g) C₁₋₄ alkenyl; (h) phenyl; (l) OCF₃, or (n)straight or branched C₁₋₆ hydroxyalkyl.
 3. The method of claim 1,wherein the group

is attached to the phenyl ring in 2-position and 3-position.
 4. Themethod of claim 1, wherein R² is —SO₂R¹.
 5. The method of claim 1,wherein R³ and R⁴ are independently H, methyl or ethyl.
 6. The method ofclaim 1, wherein R⁵ is selected from the group consisting of thefollowing chemical groups:

wherein R⁸ is H or methyl.
 7. The method of claim 1, wherein R⁶ and R⁷are independently (a) H, (b) C₁₋₆ alkyl, (c) C₃₋₇ cycloalkyl, or (d) Ar.8. The method of claim 1, wherein the compound of formula (I) isN-[2-{ethyl[(3-fluorophenyl)sulfonyl]amino}-4-(4-methyl-1-piperazinyl)phenyl]-3-fluorobenzenesulfonamide,N-[2-[ethyl(phenylsulfonyl)amino]-4-(4-methyl-1-piperazinyl)phenyl]benzenesulfonamide,3-fluoro-N-[2-{[(3-fluorophenyl)sulfonyl]amino}-4-(4-methyl-1-piperazinyl)phenyl]benzenesulfonamide,N-{5-(4-methyl-1-piperazinyl)-2-[(8-quinolinylsulfonyl)amino]phenyl}-7-quinolinesulfonamide,N-[2-chloro-4-({4-(4-methyl-1-piperazinyl)-2-[(phenylsulfonyl)amino]anilino}sulfonyl)phenyl]acetamide,3,4-dimethoxy-N-{4-(4-methyl-1-piperazinyl)-2-[(phenylsulfonyl)amino]phenyl}benzenesulfonamide,3-methoxy-4-methyl-N-{4-(4-methyl-1-piperazinyl)-2-[(phenylsulfonyl)amino]phenyl}benzenesulfonamide,4-methyl-N-{4-(4-methyl-1-piperazinyl)-2-[(methylsulfonyl)amino]phenyl}benzenesulfonamide,3,4-dimethoxy-N-{4-(4-methyl-1-piperazinyl)-2-[(methylsulfonyl)amino]phenyl}benzenesulfonamide,3-cyano-N-{4-(4-methyl-1-piperazinyl)-2-[(methylsulfonyl)amino]phenyl}benzenesulfonamide,N-{4-(1-piperazinyl)-2-[(phenylsulfonyl)amino]phenyl}-1-naphthalenesulfonamide,5-(dimethylamino)-N-{4-(1-piperazinyl)-2-[(phenylsulfonyl)amino]phenyl}-1-naphthalenesulfonamide,N-[2-[(phenylsulfonyl)amino]-4-(1-piperazinyl)phenyl]-8-quinolinesulfonamide,2,4,6-trimethyl-N-[2-[(phenylsulfonyl)amino]-4-(1-piperazinyl)phenyl]benzenesulfonamide,4-methyl-N-[2-[(phenylsulfonyl)amino]-4-(1-piperazinyl)phenyl]benzenesulfonamide,N-[2-({[(E)-2-phenylethenyl]sulfonyl}amino)-5-(1-piperazinyl)phenyl]benzenesulfonamide,2,5-dimethoxy-N-[2-[(phenylsulfonyl)amino]-4-(1-piperazinyl)phenyl]benzenesulfonamide,2-methyl-N-[2-[(phenylsulfonyl)amino]-4-(1-piperazinyl)phenyl]benzenesulfonamide,2,4-difluoro-N-[2-[(phenylsulfonyl)amino]-4-(1-piperazinyl)phenyl]benzenesulfonamide,4-butoxy-N-[2-[(phenylsulfonyl)amino]-4-(1-piperazinyl)phenyl]benzenesulfonamide,3,5-dimethyl-N-[2-[(phenylsulfonyl)amino]-4-(1-piperazinyl)phenyl]-4-isoxazolesulfonamide,5-fluoro-2-methyl-N-[2-[(phenylsulfonyl)amino]-4-(1-piperazinyl)phenyl]benzenesulfonamide,4-(methylsulfonyl)-N-[2-[(phenylsulfonyl)amino]-4-(1-piperazinyl)phenyl]benzenesulfonamide,2-(methylsulfonyl)-N-[2-[(phenylsulfonyl)amino]-4-(1-piperazinyl)phenyl]benzenesulfonamide,2-methoxy-4-methyl-N-[2-[(phenylsulfonyl)amino]-4-(1-piperazinyl)phenyl]benzenesulfonamide,4-methoxy-2-methyl-N-[2-[(phenylsulfonyl)amino]-4-(1-piperazinyl)phenyl]benzenesulfonamide,N-[2-amino-4-(1-piperazinyl)phenyl]-3-fluorobenzenesulfonamide,N-[2-(ethylamino)-4-(1-piperazinyl)phenyl]-3-fluorobenzenesulfonamide,N-{4-(1,4-diazepan-1-yl)-2-[(phenylsulfonyl)amino]phenyl}benzenesulfonamidehydrochlorideN-(4-(1,4-diazepan-1-yl)-2-{[(3-fluorophenyl)sulfonyl]-amino}phenyl)-3-fluorobenzenesulfonamidehydrochlorideN-{5-(1,4-diazepan-1-yl)-2-[(phenylsulfonyl)amino]phenyl}-N-ethylbenzenesulfonamidehydrochlorideN-{5-(1,4-diazepan-1-yl)-2-[(methylsulfonyl)amino]phenyl}benzenesulfonamidehydrochlorideN-{5-(1,4-diazepan-1-yl)-2-[(ethylsulfonyl)amino]phenyl}benzenesulfonamidehydrochlorideN-{4-(1,4-diazepan-1-yl)-2-[(phenylsulfonyl)amino]phenyl}[1,1′-biphenyl]-4-sulfonamidehydrochlorideN-{4-(1,4-diazepan-1-yl)-2-[(phenylsulfonyl)amino]phenyl}-2,1,3-benzoxadiazole-4-sulfonamidehydrochlorideN-{4-(1,4-diazepan-1-yl)-2-[(phenylsulfonyl)amino]phenyl}-2-naphthalenesulfonamidehydrochlorideN-{4-(1,4-diazepan-1-yl)-2-[(methylsulfonyl)amino]phenyl}benzenesulfonamidehydrochlorideN-{4-(1,4-diazepan-1-yl)-2-[methyl(methylsulfonyl)amino]phenyl}benzenesulfonamidehydrochlorideN-{4-(1,4-diazepan-1-yl)-2-[(methylsulfonyl)amino]phenyl}-N-methylbenzenesulfonamidehydrochlorideN-{4-(1,4-diazepan-1-yl)-2-[methyl(phenylsulfonyl)amino]phenyl}benzenesulfonamidehydrochlorideN-{4-(1,4-diazepan-1-yl)-2-[(methylsulfonyl)amino]phenyl}-1-naphthalenesulfonamidehydrochlorideN-{4-(1,4-diazepan-1-yl)-2-[(methylsulfonyl)amino]phenyl}-2-naphthalenesulfonamidehydrochlorideN-{4-(1,4-diazepan-1-yl)-2-[(methylsulfonyl)amino]phenyl}-4-fluorobenzenesulfonamidehydrochlorideN-{4-(1,4-diazepan-1-yl)-2-[(methylsulfonyl)amino]phenyl}-4-nitrobenzenesulfonamidehydrochlorideN-{4-(1,4-diazepan-1-yl)-2-[(methylsulfonyl)amino]phenyl}-3-(trifluoromethyl)benzenesulfonamidehydrochlorideN-{4-(1,4-diazepan-1-yl)-2-[(methylsulfonyl)amino]phenyl}-2-methylbenzenesulfonamidehydrochlorideN-{4-(1,4-diazepan-1-yl)-2-[(methylsulfonyl)amino]phenyl}-4-(trifluoromethoxy)benzenesulfonamidehydrochlorideN-{4-(1,4-diazepan-1-yl)-2-[(methylsulfonyl)amino]phenyl}-3,5-dimethyl-4-isoxazolesulfonamidehydrochlorideN-{4-(1,4-diazepan-1-yl)-2-[(methylsulfonyl)amino]phenyl}-3-methoxybenzenesulfonamidehydrochlorideN-{4-(1,4-diazepan-1-yl)-2-[(methylsulfonyl)amino]phenyl}-4-methylbenzenesulfonamidehydrochlorideN-{4-(1,4-diazepan-1-yl)-2-[ethyl(methylsulfonyl)amino]phenyl}-4-methylbenzenesulfonamidehydrochlorideN-{4-(1,4-diazepan-1-yl)-2-[ethyl(methylsulfonyl)amino]phenyl}-3,4-dimethoxybenzenesulfonamidehydrochlorideN-{4-(1,4-diazepan-1-yl)-2-[ethyl(methylsulfonyl)amino]phenyl}-7-quinolinesulfonamidehydrochlorideN-{4-(1,4-diazepan-1-yl)-2-[methyl(methylsulfonyl)amino]phenyl}-4-methylbenzenesulfonamidehydrochlorideN-{4-(1,4-diazepan-1-yl)-2-[methyl(methylsulfonyl)amino]phenyl}-1-naphthalenesulfonamidehydrochlorideN-{4-(1,4-diazepan-1-yl)-2-[methyl(methylsulfonyl)amino]phenyl}-5-(2-pyridinyl)-2-thiophenesulfonamidehydrochlorideN-{4-(1,4-diazepan-1-yl)-2-[(phenylsulfonyl)amino]phenyl}-1-naphthalenesulfonamidehydrochlorideN-{4-(1,4-diazepan-1-yl)-2-[(phenylsulfonyl)amino]phenyl}-5-(dimethylamino)-1-naphthalenesulfonamidehydrochlorideN-{4-(1,4-diazepan-1-yl)-2-[(phenylsulfonyl)amino]phenyl}-8-quinolinesulfonamidehydrochlorideN-{4-(1,4-diazepan-1-yl)-2-[(phenylsulfonyl)amino]phenyl}-2,4,6-trimethylbenzenesulfonamidehydrochlorideN-{4-(1,4-diazepan-1-yl)-2-[(phenylsulfonyl)amino]phenyl}-4-methylbenzenesulfonamidehydrochlorideN-[5-(1,4-diazepan-1-yl)-2-({[(E)-2-phenylethenyl]sulfonyl}amino)phenyl]benzenesulfonamidehydrochlorideN-{4-(1,4-diazepan-1-yl)-2-[(phenylsulfonyl)amino]phenyl}-2,5-dimethoxybenzenesulfonamidehydrochlorideN-{4-(1,4-diazepan-1-yl)-2-[(phenylsulfonyl)amino]phenyl}-2-methylbenzenesulfonamidehydrochloride4-butoxy-N-{4-(1,4-diazepan-1-yl)-2-[(phenylsulfonyl)amino]phenyl}benzenesulfonamidehydrochlorideN-{4-(1,4-diazepan-1-yl)-2-[(phenylsulfonyl)amino]phenyl}-3,5-dimethyl-4-isoxazolesulfonamidehydrochlorideN-{4-(1,4-diazepan-1-yl)-2-[(phenylsulfonyl)amino]phenyl}-5-fluoro-2-methylbenzenesulfonamidehydrochlorideN-{4-(1,4-diazepan-1-yl)-2-[(phenylsulfonyl)amino]phenyl}-4-(methylsulfonyl)benzenesulfonamidehydrochlorideN-{4-(1,4-diazepan-1-yl)-2-[(methylsulfonyl)amino]phenyl}-N-methylbenzenesulfonamidehydrochlorideN-{5-(1,4-diazepan-1-yl)-2-[methyl(phenylsulfonyl)amino]phenyl}-4-methylbenzenesulfonamidehydrochloride3-amino-4-(1,4-diazepan-1-yl)-N-(4-methoxyphenyl)benzenesulfonamidehydrochloride3-amino-4-(1,4-diazepan-1-yl)-N-(3-methoxyphenyl)benzenesulfonamidehydrochloride3-amino-4-(1,4-diazepan-1-yl)-N-(2-methoxyphenyl)benzenesulfonamidehydrochloride3-amino-4-(1,4-diazepan-1-yl)-N-(3-fluorophenyl)benzenesulfonamidehydrochloride3-amino-4-(1,4-diazepan-1-yl)-N-methyl-N-phenylbenzenesulfonamidehydrochloride3-amino-4-(1,4-diazepan-1-yl)-N-(4-isopropylphenyl)benzenesulfonamidehydrochloride3-amino-4-(1,4-diazepan-1-yl)-N-(4-methylphenyl)benzenesulfonamidehydrochloride3-amino-4-(1,4-diazepan-1-yl)-N-(2,5-dimethylphenyl)benzenesulfonamidehydrochloride3-amino-N-(3-chlorophenyl)-4-(1,4-diazepan-1-yl)benzenesulfonamidehydrochloride3-amino-N-(2-chlorophenyl)-4-(1,4-diazepan-1-yl)benzenesulfonamidehydrochloride3-amino-N-(2,4-dichlorophenyl)-4-(1,4-diazepan-1-yl)benzenesulfonamidehydrochloride3-amino-N-(2-methyl-5-chloro-phenyl)-4-(1,4-diazepan-1-yl)benzenesulfonamidehydrochloride3-amino-N-(2-methyl-3-chloro-phenyl)-4-(1,4-diazepan-1-yl)benzenesulfonamidehydrochloride3-amino-N-(4-trifluoro-phenyl)-4-(1,4-diazepan-1-yl)benzenesulfonamidehydrochloride3-amino-N-(4-fluorophenyl)-4-(1,4-diazepan-1-yl)benzenesulfonamidehydrochloride3-amino-N-(2-fluorophenyl)-4-(1,4-diazepan-1-yl)benzenesulfonamidehydrochloride3-amino-4-(4-methyl-1,4-diazepan-1-yl)-N-phenylbenzenesulfonamidehydrochloride 4-(1,4-diazepan-1-yl)-3-nitro-N-phenylbenzenesulfonamidehydrochloride 3-amino-4-(1,4-diazepan-1-yl)-N-phenylbenzenesulfonamidehydrochloride 2-(1,4-diazepan-1-yl)-5-(4-morpholinylsulfonyl)phenylaminehydrochloride4-(1,4-diazepan-1-yl)-N-phenyl-3-[(phenylsulfonyl)amino]benzenesulfonamidehydrochloride4-(1,4-diazepan-1-yl)-N-phenyl-3-[(methylsulfonyl)amino]benzenesulfonamidehydrochloride3-amino-N-(3-chlorophenyl)-4-(4-methyl-1-piperazinyl)benzenesulfonamidehydrochloride3-amino-N-(2-methoxyphenyl)-4-(4-methyl-1-piperazinyl)benzenesulfonamidehydrochloride3-amino-N-(2-methoxyphenyl)-4-(1-piperazinyl)benzenesulfonamidehydrochloride3-amino-N-(2-methoxyphenyl)-4-(3-methyl-1-1piperazinyl)benzenesulfonamidehydrochloride3-amino-4-(hexahydro-pyrrolo[1,2-α]pyrazin-2-yl)-N-(2-methoxyphenyl)-benzenesulfonamidehydrochloride 3-amino-N -phenyl-4-piperazin-1-yl-benzenesulfonamidehydrochloride3-amino-4-(3-methyl-piperazin-1-yl)-N-phenyl-benzenesulfonamidehydrochloride3-amino-4-(4-ethyl-piperazin-1-yl)-N-phenyl-benzenesulfonamidehydrochloride3-amino-4-(hexahydro-pyrrolo[1,2-a]pyrazin-2-yl)-N-phenyl-benzenesulfonamidehydrochloride3-amino-4-(5-methyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-N-phenyl-benzenesulfonamidehydrochloride 3-amino-4-(trans-2,5-dimethyl-piperazin-1yl)-N-(2methoxy-phenyl)benzenesulfonamidehydrochloride 2-(3-amino-4-[1,4]diazepan-1-yl-benzenesulfonyl)-benzamidediacetic acid4-[4-(3-fluoro-2-methoxy-phenylsulfamoyl)-2-amino-phenyl]-[1,4]diazepaneditrifluoroacetic acid2-[1,4]diazepan-1-yl-5-(3,4-dihydro-1H-isoquinoline-2-sulfonyl)-anilinedihydrochioride4-[4-(3,4-dihydro-2H-quinoline-1-sulfonyl)-2-amino-phenyl]-[1,4]diazepaneditrifluoroacetic acid; or3-amino-2-chloro-N-naphthalen-1-yl-4-piperazin-1-yl-benzenesulfonamide,hydrochloride.
 9. The method of claim 1, wherein the method comprisesadministering the compound of formula I, or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable diluent orcarrier.
 10. A method for the treatment of type II diabetes, the methodcomprising administering to a subject in need thereof an effectiveamount of a compound of formula (II)

or a pharmaceutically acceptable salt thereof, wherein R⁹, R¹² and R¹⁴are H; or two of R⁹, R¹² and R¹⁴ are H; and the remaining of R⁹, R¹² andR¹⁴ is (a) —NH₂, (b) —NHR⁶, (c) —NR⁶R⁷, (d) —N(CO)R⁶, (e) —N(CS)R⁶, or(f) —NO₂; R¹⁰ is a group R³; R¹¹ is a group R¹; in which each of R¹ andR³, independently, is: (a) H (b) C₁₋₆ alkyl, (c) C₁₋₆ alkoxy, (d)straight or branched C₁₋₆ hydroxyalkyl, (e) straight or branched C₁₋₆alkylhalides; or (f) a group Ar; Ar is (a) phenyl, (b) 1-naphthyl, (c)2-naphthyl, (d) benzyl, (e) cinnamoyl, (f) a 5 to 7-membered, partiallyor completely saturated, heterocyclic ring containing 1 to 4heteroatoms, selected from oxygen, nitrogen and sulfur, or (g) abicyclic ring system consisting of two heterocyclic rings as definedunder (f), or a bicyclic ring system consisting of one benzene ring andone heterocyclic ring as defined under (f); alternatively, R¹ and R³ arelinked to form a group (CH₂)₂O, (CH₂)₄O, or (CH₂)₃₋₅ in formula (Ib);optionally, the group Ar is substituted with (a) Y, or (b) a 5 to7-membered, partially or completely saturated, heterocyclic ring eachcontaining 1 to 4 heteroatoms selected from oxygen, nitrogen or sulfur;Y is (a) H, (b) halogen, (c) C₁₋₆ alkyl, (d) CF₃, (e) hydroxy, (f) C₁₋₆alkoxy, (g) C₁₋₄ alkenyl; (h) phenyl; (i) phenoxy, (j) benzyloxy, (k)benzoyl, (l) OCF₃, (m) CN, (n) straight or branched C₁₋₆ hydroxyalkyl,(o) straight or branched C₁₋₆ alkylhalides, (p) NH₂, (q) NHR⁶, (r)NR⁶R⁷, (s) NO₂, (t) —CONR⁶R⁷, (u) NHSO₂R⁶, (v) NR⁶COR⁷, (x) SO₂NR⁶R⁷,(z) —C(═O)R⁶, (aa) —CO₂R⁶, or (ab) S(O)_(n)R⁶; wherein n is 0, 1, 2 or3; R¹³ is (a) homopiperazine, (b) methylhomopiperazine, or (c) a groupR⁵; and R⁵ is selected from the group consisting of the followingchemical groups:

R⁶ and R⁷ are independently (a) H, (b) C₁₋₆ alkyl, (c) C₃₋₇ cycloalkyl,or (d) Ar, as defined above for R¹; alternatively, R⁶ and R⁷ are linkedto form a group (CH₂)₂O, (CH₂)₄O or (CH₂)₃₋₅; R⁸ is (a) H, or (b) C₁₋₆alkyl.
 11. The method of claim 10, wherein R¹³ is (a) homopiperazine,(b) methylhomopiperazine, or (c) a group R⁵ selected from

and R⁸ is (a) H, or (b) C₁₋₆ alkyl, in particular methyl; with theproviso that only one of R⁹, R¹² and R^(14 is —NH) ₂, —NHR⁶, —NR⁶R⁷,—N(CO)R⁶, —N(CS) R⁶, —NO₂; the other ones are H.
 12. The method of claim10, wherein the compound of formula (II) is:4-chloro-N-[5-(4-methyl-1,4-diazepan-1-yl)-2-nitrophenyl]benzenesulfonamide,N-[2-amino-5-(1,4-diazepan-1-yl)phenyl]benzenesulfonamide,N-[2-amino-5-(4-methyl-1,4-diazepan-1-yl)phenyl]benzenesulfonamide,N-[4-nitro-5-(piperazinyl)phenyl]benzenesulfonamide, orN-[4-amino-5-(piperazinyl)phenyl]benzenesulfonamide.
 13. The method ofclaim 10, wherein the method comprises administering the compound offormula II, or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable diluent or carrier.
 14. A method for thetreatment of type II diabetes, the method comprising administering to asubject in need thereof an effective amount of a compound of formula (I)

or a pharmaceutically acceptable salt thereof, wherein X is

R¹ and R³ are independently (a) H (b) C₁₋₆ alkyl, (c) C₁₋₆ alkoxy, (d)straight or branched C₁₋₆ hydroxyalkyl, (e) straight or branched C₁₋₆alkylhalides; or (f) a group Ar; Ar is (a) phenyl, (b) 1-naphthyl, (c)2-naphthyl, (d) benzyl, (e) cinnamoyl, (f) a 5 to 7-membered, aromatic,partially or completely saturated, heterocyclic ring containing 1 to 4heteroatoms, selected from oxygen, nitrogen and sulfur, or (g) abicyclic ring system consisting of two heterocyclic rings as definedunder (f), or a bicyclic ring system consisting of one benzene ring andone heterocyclic ring as defined under (f); alternatively, R¹ and R³ arelinked to form a group (CH₂)₂O, (CH₂)₄O, or (CH₂)₃₋₅ in formula (Ib);optionally, the group Ar is substituted with (a) Y, or (b) a 5 to7-membered, partially or completely saturated, heterocyclic ring eachcontaining 1 to 4 heteroatoms selected from oxygen, nitrogen or sulfur;Y is (a) H, (b) halogen, (c) C₁₋₆ alkyl, (d) CF₃, (e) hydroxy, (f) C₁₋₆alkoxy, (g) C₁₋₄ alkenyl; (h) phenyl; (i) phenoxy, (j) benzyloxy, (k)benzoyl, (l) OCF₃, (m) CN, (n) straight or branched C₁₋₆ hydroxyalkyl,(o) straight or branched C₁₋₆ alkylhalides, (p) NH₂, (q) NHR⁶, (r)NR⁶R⁷, (s) NO₂, (t) —CONR⁶R⁷, (u) NHSO₂R⁶, (v) NR⁶COR⁷, (x) SO₂NR⁶R⁷,(z) —C(═O)R⁶, (aa) —CO₂R⁶, or (ab) S(O)_(n)R⁶; wherein n is 0, 1, 2 or3; R² and R⁴ are independently: (a) —SO₂R¹, (b) H, (c) C₁₋₆ alkyl, (d)C₁-C₃ alkenyl, (e) C₁-C₃ alkylaryl, (f) Ar as defined above for R¹, (g)—C(═O)R⁶, (h) —C(O)NR⁶R⁷, (i) —C(S)NR⁶R⁷, (j) —CO₂R⁶; (k) —C(S)R⁶; (l)straight or branched C₁₋₆ hydroxyalkyl, or (m) straight or branched C₁₋₆alkylhalides; alternatively, R² and R⁴ are linked to form a group(CH₂)₂O, (CH₂)₄O, or (CH₂)₃₋₅ in formula (Ia); R⁵ is selected from thegroup consisting of the following chemical groups:

R⁶ and R⁷ are independently (a) H, (b) C₁₋₆ alkyl, (c) C₃₋₇ cycloalkyl,or (d) Ar, as defined above for R¹; alternatively, R⁶ and R⁷ are linkedto form a group (CH₂)₂O, (CH₂)₄O or (CH₂)₃₋₅; R⁸ is (a) H, or (b) C₁₋₆alkyl.
 15. The method of claim 14, wherein Ar is a 5 to 7-memberedaromatic heterocyclic ring containing 1 to 4 heteroatoms, selected fromoxygen, nitrogen and sulfur.
 16. The method of claim 14, wherein Ar isisoxazolyl, benzoxadiazolyl, quinolinyl, or thienyl.